Clinical trial NCT01457352
Conditions: Spasticity
Keywords: spasticity
Sponsor: Sun Pharma Advanced Research Company Limited
Start date: 2012-11-14; Completion date: 2017-08-25
Enrollment: 392 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess whether SPARC0921 demonstrate efficacy and safety in the treatment of spasticity.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: SPARC0921 intervention 2: Placebo0921
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Study title:  
A placebo-controlled randomized withdrawal evaluation of the efficacy and safety of Baclofen ER GRS 
capsules in subjects with spasticity due to mltiple scerosis 
Protocol number:
CLR_09_21 dated 24 Feb 2012
NCT number: NCT01457352


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PROTOCOL 
A PLACEBO-CONTROLLED RANDOMIZED WITHDRAWAL EVALUATION OF THE
EFFICACY AND SAFETY OF BACLOFEN ER CAPSULES (GRS)
 IN SUBJECTS WITH
SPASTICITY DUE TO MULTIPLE SCLEROSIS 
Protocol No.  
: CLR_09_21 
Version No./Date  
: 07/ 24 Feb 2012 
Amendment No./Date 
: 0 
Investigational Product : Test: 
Reference:  
Study Phase  
: 3 
Sponsor 
: Sun Pharma Advanced Research Company Ltd., 
17/B, Mahal Industrial Estate, 
Mahakali Caves Road, 
Andheri (E), Mumbai 400 093, 
India. 
Confidentiality Statement 
This protocol is a confidential document owned by Sun Pharma Advanced Research Company Ltd., India (SPARC 
Ltd.).  Any unpublished information contained in it may not be disclosed to a third party without prior written approval 
of SPARC Ltd., India.  However, the document may be disclosed to an Institutional Review Board, an Independent 
Ethics Committee or a statutory regulatory authority under a similar condition of confidentiality. 


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PROTOCOL SYNOPSIS 
Title: 
 
A Placebo-Controlled Randomized Withdrawal Evaluation of the Efficacy and Safety of 
Baclofen ER Capsules (GRS) in Subjects with Spasticity Due to Multiple Sclerosis 
 
 
Study Design: 
This 21-week study will be performed in three parts:  
 
(Part 1) 
: Open-label, run-in 
 
 
 
(Part 2) 
: Open-label part in which subjects are converted to the corresponding dose of 
 
 
 
 
 
(Part 3) 
: Double-blind
 
 
 
 
) 
 
 
A 
 
  Subjects will be encouraged to come 
for one additional unscheduled visit during this interval in order to
 
. 
 
The schedule of assessments is provided in Table 1. 
 
 
Objectives:  
Primary Objectives: 
The primary objectives are to compare the continued treatment with 
 
 
 
  
 Demonstrating efficacy 
 
 Indirectly demonstrating 
 
 Determining the safety 
 
 
Secondary Objectives: 
To determine effects on other corollary measures of spasticity such as: 
 Subject‟s assessment of spasticity severity 
 
Exploratory Objectives: 
The following will be explored: 
 
  
 
 
 
 
 Effect of concomitant medication use and disease characteristics on   
 
 
 
 
Primary Efficacy 
Outcome:  
The primary efficacy outcome is the proportion of subjects who become a treatment failure 
during double-blind randomized withdrawal (Part 3).  Each subject‟s response will be 
determined after database lock, but prior to unblinding the data.  A
 subject who meets the 
following criterion will be considered a treatment failure: 
  
  
A CGIC of ≥ 5 (“minimally worse” to “very much worse”) and at least one movement 
with a ≥ 1 unit increase 1 in modified Ashworth score from baseline 
                                                 
1 A change from 1 to 1+ and 1+ to 2 will be counted as a 1-unit change 


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The modified Ashworth score will be assessed at each clinic visit, recorded for each of the 12 
movements evaluated.  The Baseline score against which worsening will be determined  
 
 
   
 
For the primary efficacy analysis, subjects who provide modified Ashworth and CGIC scores 
at Visit 11 and meet the treatment failure criterion at Visit 11, or who have met the treatment 
failure criterion at any prior visit 
) will be classified as being treatment 
failures.  All other subjects will be classified as not being treatment failures.   
 
Secondary Efficacy 
Outcomes: 
Subject Global Impression of Severity (SGIS)  
 
Safety Assessments: 
 
 Treatment Emergent Adverse Events 
 Daytime sedation 
 Vital Signs (seated blood pressure and pulse) 
 Clinical laboratory tests 
 12 Lead ECG 
 Physical examination and neurological evaluation 
 Columbia – Suicide Severity Rating Scale 
 
 
Treatments: 
 
 
 
 
 
 
 
 
 
Study Population: 
Subjects aged 18 years and above with spasticity due to multiple sclerosis with acceptable 
symptom control 
 
 
. 
 
 
Number of Subjects: Approximately 300 subjects will be enrolled to ensure that at least 240 subjects are randomized 
at the beginning of 
 
 
.   
 
 
Number of Centers: Up to 35 centers  
 
 
Setting: 
Out-patient clinics  
 
 
Statistical Methods:  
 
Efficacy Analyses: 
The primary efficacy analysis will be performed on an intent-to-treat (ITT) population, defined 
as all subjects who were randomized to double-blind study drug at Visit 7 and subsequently 
received at least one dose of study medication.  
 
 
 
).   
 
A
 per protocol (PP) population may also be analyzed (if it differs from the ITT population 
overall by more than 10% in sample size), defined as all ITT population subjects who had at 
least one on-treatment assessment in Part 3, and did not have any major protocol violation 
(such as poor compliance).  
 
 
 


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. 
 
Sensitivity analyses of the primary endpoint will be performed.  These will include 
 
 
 
n.   
 
The secondary efficacy outcome is Subject Global Impression of Severity (SGIS).  The change 
in the SGIS from Visit 7 (reference) to Visit 11 will be analyzed using the Mantel-Haenszel test 
stratified by stabilized dose level.  
 
 
. 
 
   
     
     
  
   
   
  
  
  
. 
 
Safety Analyses: 
The incidence of treatment-emergent AEs (TEAEs) and SAEs will be summarized for the 
open-label 
 dose conversion / fixed dose phases  
, and also by 
treatment group during the randomized withdrawal phase (Part 3).  A
 TEAE is defined as any 
event with an onset after the first dose received in a given study phase or that was pre-existing 
but worsened in severity or increased in treatment attribution; for the randomized withdrawal 
part, emergent events will be summarized by randomized double-blind treatment group.  
Adverse events reported as pre-existing prior to run-in  
 treatment or that emerge 
during the  
 treatment phase will be considered pre-treatment adverse events.  The 
incidence of TEAEs will be presented by system organ classification and preferred terms 
according to the Medical Dictionary for Regulatory Activities (MedDRA
®), by causality, by 
severity
, and by action taken.  Analyses of subjects grouped by demographic, baseline disease 
characteristics, and concomitant medication use will also be undertaken. 
 
 
 
 
. 
 
Prior and concomitant medications will be coded using WHODRUG and will be summarized 
using counts and percentages.  Possible anti-spasticity medications will be identified during 
blinded data review; these will be summarized separately. 
 
Vital sign measurements (sitting systolic and diastolic blood pressures and resting pulse) and 
clinical laboratory testing results at each visit will be summarized using descriptive statistics.  
Criteria for possibly clinically significant changes will be established a priori.  Summary of 
vital signs and laboratory measurements with clinically significant changes will be provided. 
 
ECG interval data and ventricular rate will be summarized at each time point, both as absolute 
values and as change from Visit 2.  Criteria for possibly significant values and changes will be 
established a priori.  
 
Physical examination and neurological evaluation findings will be summarized.  These will be 
reviewed for any emergent abnormalities that could be attributed to the new dosage form.   
 
Columbia – Suicide Severity Rating Scale (C-SSRS) will be used to assess suicidality. 
 
Subject listings will be provided for all safety parameters as well as recently and concurrently 
used medications. 
 








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6.1  Study Medication(s) including Name(s), Dose(s), Dosing Schedule(s), Route(s), 
Treatment Period(s), Follow-up Period(s) 
............................................................................. 36 
6.2  
Medication(s)/Treatment(s) Permitted and Not Permitted Before and/or During the 
Study 37 
6.2.1 Medication(s) Permitted.................................................................................. 37 
6.2.2 Concomitant Medication Restriction 
.............................................................. 37 
6.2.3 Dietary Restrictions ........................................................................................ 38 
6.3  Procedure(s) for Monitoring Subject Compliance 
..................................................... 38 
6.4  Accountability Procedures for the Investigational Product 
....................................... 38 
6.5  
Maintenance of Study Treatment Randomization Codes and Procedures for Breaking 
Codes 39 
7  
WITHDRAWAL AND REPLACEMENT RULES 
.......................................................... 39 
7.1  
Withdrawal 
................................................................................................................ 39 
7.1.1 Premature Discontinuation of Subject in the Study 
........................................ 39 
7.1.2 Early Stopping of the Study 
............................................................................ 40 
7.2  Replacement 
.............................................................................................................. 40 
8  
ASSESMENT OF EFFICACY AND PHARMACOKINETICS 
..................................... 40 
8.1  Description of Efficacy Parameters 
........................................................................... 40 
8.1.1 Primary Efficacy Parameter(s) 
........................................................................ 40 
8.1.2 Secondary Efficacy Parameter(s) 
.................................................................... 42 
8.1.3 Exploratory Parameters 
................................................................................... 42 
8.2  
Methods and Timing for Assessing and Recording Efficacy Parameters 
.................. 43 
8.3  Pharmacokinetics 
................................
....................................................................... 43 
8.3.1 Time Points/Intervals for Collection of Pharmacokinetic Samples 
................ 43 
8.3.2 Sample Handling and Shipping ...................................................................... 44 
8.3.3 Bioanalytical Method 
...................................................................................... 44 
9  
ASSESSMENT OF SAFETY 
.............................................................................................. 44 
9.1  Description of Safety Parameters............................................................................... 44 
9.1.1 Adverse Event 
................................................................................................. 45 
9.1.2 Serious Adverse Event 
.................................................................................... 45 
9.1.3 Pregnancy 
....................................................................................................... 46 
9.2  
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
. 46 
9.2.1 Eliciting, Documentation and Reporting of Adverse Events and Intercurrent 
Illnesses 
...................................................................................................................... 46 
9.2.2 Daytime Sedation 
............................................................................................ 49 
9.2.3 Concomitant Medication and Physiotherapy Recording 
................................ 50 
9.2.4 Vital Sign Measurement ................................................................................. 50 
9.2.5 Clinical Laboratory Testing 
............................................................................ 50 
9.2.6 12-Lead ECG 
.................................................................................................. 51 
9.2.7 Physical Examination...................................................................................... 51 
9.2.8 Neurological Examination 
.............................................................................. 51 
9.2.9 Columbia – Suicide Severity Rating Scale (C-SSRS) 
.................................... 52 
10 
STATISTICAL CONSIDERATIONS 
............................................................................... 52 
10.1 Primary and Secondary Efficacy Variables 
............................................................... 52 
10.2 Sample Size 
................................................................................................................ 52 
10.3 Study Populations 
................................
...................................................................... 53 


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10.3.1 Efficacy Populations 
..................................................................................... 53 
10.3.2 Safety Population 
.......................................................................................... 54 
10.4 Statistical Methods 
..................................................................................................... 54 
10.4.1 Demographic and Other Baseline Characteristics ........................................ 54 
10.4.2 Study Disposition and Dosing 
....................................................................... 55 
10.4.3 Efficacy Analysis 
.......................................................................................... 56 
10.4.4 Pharmacokinetic Analysis 
............................................................................. 59 
10.4.5 Safety Analysis ............................................................................................. 59 
10.4.6 Prior and Concomitant Medications ............................................................. 62 
10.5 Unblinding 
................................................................................................................. 62 
10.6 Level of Significance 
................................................................................................. 62 
10.7 
Missing Data 
................................
.............................................................................. 63 
10.8 Procedures for Reporting Protocol Violations/Deviations ........................................ 63 
11 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
............................................... 63 
11.1 
Monitoring 
................................................................................................................. 63 
11.2 Documentation at the Study Site................................................................................ 63 
11.3 Subject
's Data and Data Protection 
............................................................................ 64 
11.4 Data Management and Analysis 
................................................................................ 64 
11.5 Amendments to the Protocol 
...................................................................................... 65 
11.5.1 Emergencies 
.................................................................................................. 65 
11.5.2 Protocol Violations/ Deviations 
.................................................................... 65 
12 
QUALITY CONTROL AND QUALITY ASSURANCE 
................................................. 66 
13 
ETHICS ................................................................................................................................ 66 
13.1 Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
............. 66 
13.2 Ethical Conduct of the Study 
..................................................................................... 66 
13.3 Subject Information and Consent............................................................................... 66 
14 
DATA HANDLING AND RECORD KEEPING 
.............................................................. 67 
15 
FINANCING AND INSURANCE 
...................................................................................... 67 
16 
PUBLICATION POLICY 
................................................................................................... 67 


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LIST OF ABBREVIATIONS 
 
Abbreviation  
Expanded Form 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT (SGPT) 
Alanine aminotransferase (Serum Glutamate Pyruvic Transaminase) 
ANCOVA 
Analysis of Covariance 
AST (SGOT)  
Aspartate aminotransferase (Serum Glutamate Oxaloacetate Transaminase) 
BUN 
Blood Urea Nitrogen 
°C 
C-CASA 
Degree (Celsius) 
Columbia Classification Algorithm of Suicide Assessment 
 
 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CRF 
Case Record Form/ Case Report Form 
CRO 
C-SSRS 
Contact Research Organization 
Columbia – Suicide Severity Rating Scale 
DCF 
Data Clarification Form 
DCGI 
Drugs Controller General of India 
EC 
Ethics Committee 
ECG 
Electro-Cardiogram 
 
 
e.g. 
For example 
 
 
GABA 
Gamma- Amino-Butyric Acid 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transpeptidase 
GLUC 
Glucose 
GMP 
Good Manufacturing Practice 
GRS 
Gastro-Retentive System 
Hb 
Hemoglobin 
HDPE 
High Density Poly-Ethylene 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator‟s Brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
 
 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
IUD 
Intra-Uterine Device  
IVRS 
IWRS 
Interactive Voice Response System 
Interactive Web Response System 
LOCF 
Last Observation Carried Forward 
MAOI 
Monoamine Oxidase Inhibitor 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
MS 
Multiple Sclerosis 
nSAE 
Non-Serious Adverse Event 
OD 
Once Daily (every 24 hours) 
SGIS  
Subject Global Impression of Severity 
PI 
Principal Investigator 
PP 
Per Protocol 
QC 
Quality Check 


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R&D 
Research and Development 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOPs 
Standard Operating Procedures 
SPARC Ltd. 
Sun Pharma Advanced Research Company Limited 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
 
 
UTI 
Urinary Tract Infection 
ULN 
VAS 
Upper Limit of Normal  
Visual Analogue Scale 
WBC 
White Blood Cell 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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1.5 Investigator Responsible for Conducting the Study and Study Site(s) 
Name 
:  
Title 
:  
Address 
:  
Phone 
:  
Fax 
:  
Mobile 
:  
 
 
 
 
 
 
  
 
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
 
  
 
  
 
  
 
  
 
 
 
  
 
  
 
  
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
Signature 
 
Date (dd mmm yyyy) 
 
 


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2 BACKGROUND INFORMATION 
 
   
 
 
 
  
  
 
  
 
 
  
 
 
   
 
  
 
 
  
 
   
 
 
 
 
  
 
 
  
 
  
 
 
 
  
 
  
 
 
 
 
  
 
 
 
2.1 Investigational Product 
2.1.1 Name and Description 
 
  
 
 
 
 
  
  
 


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The terms study  drug, study medication, study treatment 
have been used interchangeably throughout the document to denote investigational product. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
2.1.2 Clinical Data to Date for 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
    
 
 
 
 
 


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2.2 Summary of the Known and Potential Risks and Benefits, If Any, to Human 
Subjects 
 
   
 
The most common adverse effects are 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
2.3 Description of the Justification for the Route of Administration, Dosage, Dosage 
Regimen, and Treatment Period(s) 
  
 
 
  
 
  
 


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2.4 Compliance Statement for Study Conduct in Accordance with Protocol, GCP and 
Applicable Regulatory Requirements 
The study protocol, amendments to the protocol (if applicable), the IB (Investigator‟s Brochure), 
subject recruitment procedures (e.g., advertisements), and the subjects
' information and informed 
consent form as well as consent form updates (if applicable) will be submitted to the IRB/IEC, which is 
constituted according to local law to obtain approval before initiation of the study and as applicable 
thereafter. 
 
The study will only be initiated after receipt of the approval from the IRB/IEC.  The Investigator will 
report promptly to the IRB/IEC new information that may adversely affect the safety of the subjects or 
the conduct of the study.  
 
The Investigator will follow the protocol in conformity with Good Clinical Practice (GCP) 
described in Guideline E6 of the ICH and applicable regulatory requirements.  


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Before admission into the study, the written informed consent form must be signed and personally 
dated by the subject and by the Investigator or designee who conducted the informed consent 
discussion. In obtaining and documenting informed consents, the Investigator must comply with the 
applicable regulatory requirement(s), and must adhere to GCP. 
 
The Investigator must inform the subject of all pertinent aspects of the study including the written 
information approved/favorably assessed by the IRB. 
 
2.5 Description of the Study Population 
Subjects 18 years of age and older, with an established diagnosis of Multiple Sclerosis,   
 
 
  
 
 
 
 
2.6 References to Literature and Data that are Relevant to the Study 
1. 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
   
 
  
 
  
 
 
 
  
 
 
 
3 STUDY OBJECTIVES AND PURPOSE 
3.1 Primary Objectives 
The primary objectives are to compare the continued treatment with 
 
 for the 
purposes of: 


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 Demonstrating efficacy of 
 
 Indirectly demonstrating 
 
 Determining the safety profile 
 
 
3.2 Secondary Objectives 
To determine effects on another corollary measure of spasticity such as: 
 Subject‟s assessment 
 
 
3.3 Exploratory Objectives 
The following will be explored: 
 
  
 
 
 
 
 Effect of concomitant medication use and disease characteristics     
 
 
 
4 STUDY DESIGN 
4.1 Description of Type and Design of Study  
The study is a 21-week (exclusive of screening) multicenter, out-patient trial in subjects with 
spasticity due to MS that is 
.  The study will 
be performed in three parts:  a 
 (Part 1) in which subjects receive  
 
 a   
 
Part 2) in which subjects are, 
 
 
 and a 4-week, double-blind, placebo-controlled, 
 
(Part 3).  Subjects will be informed that at some time during the study
, they may receive placebo, 
however, they will not be informed at which visit this will commence.  An overview scheme of the 
study is presented below
. 
 


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Schema of Study Visits and Corresponding Study Week and Day 
 
Part 
1 
Part 2 
Part 3 
Open-label 
Double-Blind 
  
 
 
 
 
C
 
  
 
 
 
Placebo-controlled,  
Down-titration Phase 
(4 weeks) 
Visit Number 
1  2 (T) 3 (T) 4  
(T)  
5  
(T)  
6  
(T)  
7  
8  
9  
10  
11 
Beginning of Study Week 
1  2 3  4  5  6 7 8 9 10 1
1 
1
2 
1
3 
14 15 16  17  
18  
19  20  
21  
-- 
Corresponding Study Day 
1  8 15 22 29 36    64       92    
  
  
120  127 
134  141  148 
   
 
 


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Approximately 300 subjects will be enrolled to ensure that at least 240 subjects are randomized in 
Part 3; 
e.  Subjects will be screened for eligibility 
within 14 days of the initial visit by medical history
, recent and concomitant medication use, 
physical and neurological examination, 12-lead ECG
, clinical laboratory testing, and assigned a 
subject number
.  Upon successful screening and provision of informed consent, eligible subjects 
will be enrolled in the study (Visit 1).  .  Once on study
, subjects will be seen in the clinic at the end 
of the 7-day  
 run-in (Visit 2), at which point they will be converted to  
 
 (described in Section 4.3.1).  They will be seen in the clinic every 2 weeks during 
the 
 
; subjects are to be contacted by telephone during the intervening weeks 
).  As described in Section 4.3.1, dose adjustments 
will be allowed during this 4-week phase; dose adjustments may only be made at a clinic visit, 
including at an unscheduled meeting if needed.  
 
 
 
   
 
At the beginning of   
 (Visit 7), subjects who have remained on a fixed dose of  
 
, without further need for adjustment in medication, will be 
randomly assigned to either remain on 
 
In subjects 
 
  All subjects will be seen in the clinic 
every week (see Table 1) or sooner, if required.  
 
  The final scheduled 
study visit is 
  Subjects will be encouraged to continue 
study participation to the end of the trial.  In subjects 
 
   
 
Subjects will be instructed to take study drug at the same time of day
, 30 minutes following the 
evening meal.  Throughout the study
, clinic visits should be timed to occur at approximately the 
same time of day relative to dosing.  Clinic conditions, e.g., ambient temperature and lighting, 
should be kept as consistent as possible.  Similarly
, concomitant physiotherapy should also not 
change during the course of the study
.   
 
Subjects will be evaluated for efficacy as briefly described below
.  The efficacy instruments and 
assessments are further described in Section 8.1.   
 
 
 
 
.  Right and left hip flexion 
and abduction, knee flexion and extension, and ankle dorsiflexion and plantar flexion will be 
assessed using the modified Ashworth Scale, 
 
  
 
  The modified Ashworth Scale assessment is further 


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discussed in Section 8.1.1.1. 
 Clinician Global Impression of Change (CGIC) will be assessed by the Treating Physician, i.e., 
an evaluator other than the one performing the Ashworth assessment; the CGIC will be 
 
 
  
 The Subject Global Impression of Severity (SGIS) over
 
. 
 
In addition, subjects will fill out a daily diary throughout the study assessing the following:  
 
 
 
 
 
 
 
 
 
 
 
During the course of the study
, subjects will be monitored for adverse events and vital signs (seated 
blood pressure and pulse) measured at each clinic visit. Suicidality will be assessed at every visit 
using C-SSRS.  Clinical laboratory testing will be repeated at the end of the open-label phase,  
 
 after all subjects have received 
 
, and if needed, a
.  ECGs will be recorded at 
screening, after subjects have completed the 1-week Baclofen IR run-in (Visit 2), after 
subjects have received 
 for 4 weeks (Visit 4), after subjects have 
received
 for 18 weeks (Visit 7), and if needed, at Week 22 (Visit 11) 
or early termination.  Physical and neurological evaluation will be performed at screening and if 
needed, at Week 22 (Visit 11) or early termination.   
 
At the final visit 
 clinical laboratory testing, ECG 
measurement, and physical and neurological evaluation will be performed if needed.  Any 
treatment-emergent abnormalities shall continue to be evaluated with testing as needed to follow 
resolution.   
 
Subjects will be instructed that even though they may have extra medication, they should return to 
the clinic for their visits according to the schedule included in Section 4.4.   
 
Subjects who enter 
(Part 3) will be offered the 
opportunity to participate in a separate open-label trial o
    
 
4.2 Measures Taken To Avoid Bias 
4.2.1 Subject Number 
At  Screening, after signing informed consent form, each subject will be allotted a unique 6-digit 
number
.  This number will be noted on the electronic case report form (eCRF). 




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.   
 
o 
 
: 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
o 
 
      Subjects will be allowed 
, 
     
 
  
For purposes of determining how subjects are converted, the 
 
 
  Whenever a dose   
 
 
 
 
  
 
 
 
 


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* 
 
 
.   
 
 
o 
  
Subjects will continue on 
 
, such that total exposure to 
.  If a dose 
adjustment is required during this phase either due to poor tolerance or worsening spasticity, the 
subject will be discontinued; such a subject will not be offered participation in the separate 
open-label study of 
   
 
o
 
Subjects will be randomly assigned to remain on their fixed 
 
 
 
 
 
 
 
  
 
  
 
 
   
 


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4.3.2 Dispensing (Labeling and Packaging) and Compliance 
ill be performed by 
 
respectively.  Details of packaging are briefly described here and will be elaborated on in a separate 
packaging and distribution protocol.  Drug will be 
 
 
 
The 
 
 
  
 
 
 
The 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
The study medication will be 
 
  
 




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4.3.4 Study Medication Numbering 
 
. 
 
4.4 
 
 
   
4.4.1 
 
 Informed consent  
 Demographic details 
 Medical and  medication history  
 Physical examination  
 Neurological examination 
 'Resting pulse and blood pressure measurement (sitting) 
 ECG 
 Clinical laboratory testing 
 Urine pregnancy test 
 Modified Ashworth score  
 Adverse events assessment 
  
 
 Concomitant medication record and description of current physiotherapy regimen 
 Blood sample for baclofen plasma concentrations 
 
4.4.2 Study Part 1 
 
4.4.2.1 Visit 1 
 
 Medical and Medication history 
 'Restingpulse and blood pressure measurement (sitting) 
  
 
 
 
 Dispense subject diary 
 Modified Ashworth score  
 Adverse events assessment 
  
 
 Concomitant medication record and whether or not there is a change in physiotherapy 
regimen 
 
4.4.3 
 
4.4.3.1 
 
4.4.3.1.1 
 






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 'Resting pulse and blood pressure measurement (sittin
g) 
 Dispense 
 
 Collect and dispense subject diary 
 
  
 Adverse events assessments 
  
 
 Assess 
 
 Concomitant medication record and whether or not there is a change in physiotherapy 
regimen 
 Blood sample for baclofen plasma concentrations 
 
4.4.3.2.4 
 
If the unscheduled visit is 
 
 
. If an unscheduled visit is required for another reason (other than 
blood collection for plasma baclofen concentration), the following evaluations should be done.  
 'Resting pulse and blood pressure measurement (sitting) 
 Collect and dispense subject diary 
 Modified Ashworth score  
 Adverse events assessment 
 C-SSRS 
 Assess double-blind medication compliance 
 Concomitant medication record and whether or not there is a change in physiotherapy 
regimen 
 
 
 
 
 
 
 
 
 
 
 
4.4.4 Study Part 3 (4-week, double-blind, placebo-controlled): 
4.4.4.1 Visit 7 (Week 18, Day 120 ± 1 day)  
 'Resting pulse and blood pressure measurement (sitting) 
 ECG 
 Clinical laboratory testing 
 Urine Pregnancy Test 
 Randomization to 
 
 Dispense double-blind medication pack for 28 (+4) days 


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 Collect and dispense subject diary 
 Modified Ashworth score  
 CGIC relative 
and SGIS over prior week 
 Adverse events assessment 
 C-SSRS 
 Assess Baclofen ER Capsules (GRS) compliance 
 Concomitant medication record and whether or not there is a change in physiotherapy 
regimen  
 
 
 
4.4.4.2 Visit 8 (Week 19, Day 127 ± 1 day) 
 'Resting pulse and blood pressure measurement (sitting) 
 Collect and dispense subject diary 
 Modified Ashworth score  
 CGIC 
and SGIS over prior week 
 Adverse events assessment 
 C-SSRS 
 Assess double-blind medication compliance 
 Concomitant medication record and whether or not there is a change in physiotherapy 
regimen 
 
4.4.4.3 Visit 9 (Week 20, Day 134 ± 1 day) 
 'Resting pulse and blood pressure measurement (sitting) 
 Collect and dispense subject diary 
 Modified Ashworth score  
 CGIC 
 and SGIS over prior week 
 Adverse events assessment 
 C-SSRS 
 Assess double-blind medication compliance 
 Concomitant medication record and whether or not there is a change in physiotherapy 
regimen 
 
4.4.4.4 Visit 10 (Week 21, Day 141 ± 1 day) 
 'Resting pulse and blood pressure measurement (sitting) 
 Collect and dispense subject diary 
 Modified Ashworth score  
 CGIC 
 and SGIS over prior week 
 Adverse events assessment 
 C-SSRS 
 Assess double-blind medication compliance 


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 Concomitant medication record and whether or not there is a change in physiotherapy 
regimen 
 
4.4.4.5 
 
 Physical examination (as needed to follow adverse events to resolution) 
 Neurological examination (as needed to follow adverse events to resolution) 
 'Resting pulse and blood pressure measurement (sitting) 
 Clinical laboratory testing (as needed to follow adverse events to resolution) 
 Urine pregnancy test (as needed) 
 ECG (as needed to follow adverse events to resolution) 
 Collect subject diary 
 Modified Ashworth score  
 CGIC 
 and SGIS over prior week 
 Adverse events assessment 
 C-SSRS 
 Assess double-blind medication compliance 
 Concomitant medication record and whether or not there is a change in physiotherapy 
regimen 
 
5 SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1 Inclusion Criteria  
Approximately 300 subjects with known history of   
due to multiple sclerosis, treated with 
a stable dose of   
are to be enrolled.  Subjects are required to consent to participate in the 
study.  They will be informed that their primary medical practitioner and physiotherapist may be 
contacted to inform them of the study and its conditions.  Subjects must fulfill inclusion/exclusion 
criteria as listed below. 
 
1. Men and women age 18 years and older 
2. Women of child bearing potential practicing an acceptable method of birth control for the 
duration of the study as judged by the investigator(s) [such as condoms, foams, jellies, 
diaphragm, intrauterine device (IUD), oral or long acting injected contraceptives, bilateral tubal 
ligation or vasectomized partner] for at least 3 months prior to study entry OR postmenopausal 
for at least 1 year OR surgically sterile (bilateral oophorectomy or hysterectomy) 
3. If female, negative pregnancy test 
4. 
 
 
 
 
 
 
 
 


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7. Has an ECG that is not clinically significantly, abnormal and a blood pressure <160/95 mmHg 
(systolic/diastolic) at screening, measured in the sitting position after approximately 5 minutes 
of quiet rest 
8. If the subject has a history of or presence of clinically significant liver disease, diabetes 
mellitus, hypertension or heart disease, the subject must be on a stable treatment regimen for a 
minimum of 3 months prior to Screening Visit  
9. Able and willing to comply with the protocol, including availability for all scheduled clinic 
visits  
10. Willingness and giving of written informed consent 
 
5.2 Subject Exclusion Criteria 
1. 
 
 
  
3. Concomitant neurologic conditions causing spasticity (e.g., stroke, cerebral palsy, traumatic 
brain injury) or rigidity (e.g., Parkinson‟s disease, contractures that confound assessment of 
spasticity) 
4. Advanced arthritis or any other cause of clinically significant limitation of passive range of 
motion around any of the joints being assessed in this study 
5. Any medical condition, including psychiatric disease or epilepsy, which would interfere with 
the interpretation of the study results, the conduct of the study, or the safety of the subject 
6. 
 
  
7. History of alcohol abuse or use of recreational drugs within 12 months prior to the Screening 
Visit 
8. 
 
 
 
  
 
 
 
  
 
 
   
 
 
 
 
  
11. Unable to comply with study procedures in the opinion of the investigator 
12. 
 
 
 
13. Has had major surgery within 3 months prior to Screening visit that may affect spasticity 
assessments such as abdominal surgery, back surgery, or lower leg or knee surgeries 
 
5.3 Subject Withdrawal Criteria 
The subject will receive oral and written information about the study, which includes information 
about the right to withdraw from the trial at any time without prejudice to future treatment. In this 
case, the subject must immediately contact the Investigator and state that he/she is leaving the study.  
The subject will be encouraged to provide the reason for wishing to withdraw.  The subject must 
return the study drug as well as undergo final study visit procedures. 


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The Investigator must withdraw a subject from the study in the following cases: 
 
 
 
 
 
 
The following are additional justifiable reasons for removing a subject from the study: 
 There is need for further Baclofen ER Capsules (GRS) dose change after the first 4 weeks 
 Subject experiences intolerable spasticity 
 Subject has a treatment related serious adverse event (SAE) 
 Subject gets pregnant during the study 
 If, in the Investigator‟s opinion, continuation in the study would be detrimental to the 
subject‟s we
ll-being 
 
6 TREATMENT OF SUBJECTS 
6.1 Study Medication(s) including Name(s), Dose(s), Dosing Schedule(s), Route(s), 
Treatment Period(s), Follow-up Period(s) 
Study Medication For : Part 1 (1-week open-label) 
Study Medication  
: 
 
Formulation 
: Tablet 
Dose strength in mg  
: 
 
Dosing schedule  
: 
 
Route of administration : Oral 
Treatment period  
: 1 week 
 
  
Study Medication For : Part 2 (16-week open-label) 
Study Medication  
: 
 
Formulation 
:  
 
Dose strength in mg  
: 
 
Dosing schedule  
: 
l 
Route of administration : Oral 
Treatment period  
: 16 weeks 
 
  
Study Medication For : Part 3 (4-week double-blind, placebo-controlled) 
Study Medication  
: 
 
Formulation 
:  
 
Dose strength in mg  
: 
 
Dosing schedule  
: 
 
Route of administration : Oral 
Treatment period  
: 4 weeks 
Follow-up 
: Until end of study part 3 or until resolution of adverse event, whichever 
is later 
 
Subjects will be instructed that 
 
 
. 


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6.2 Medication(s)/Treatment(s) Permitted and Not Permitted Before and/or During 
the Study 
All subjects will be questioned about the use of any pre-study and concomitant medication.  All 
concomitant treatments must be appropriately recorded and described in the eCRF.   
6.2.1 Medication(s) Permitted 
Medications permitted would be other than those mentioned in Section 6.2.2, after consulting with 
the Investigator.  These will be recorded as concomitant medications. 
 
6.2.1.1 
 
  
 
 
 
  
 
 
 
.   
 
This list of medications includes the following:   
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
 
As antacids may affect the release of baclofen from the GRS capsule by the same mechanism, it is 
recommended that subjects refrain from taking antacids within 2 hours before or after taking study 
medication.   
 
6.2.2 Concomitant Medication Restriction 
6.2.2.1 
 
 
 
 
 
 


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During the blinded review (to be explained in detail in the statistical analysis plan (SAP)) prior to 
database lock and unblinding, concomitantly used medications will be reviewed and any that have 
potential anti-spasticity effects will be identified.  The dose and time of use relative to the efficacy 
 list of medications that affect spasticity includes (but is not limited 
to) the following:   
 Benzodiazepines  
 Anti-spasticity medications:  Tizanidine, fampridine/ dalfampridine  
 Muscle relaxants:  Cyclobenzaprine, metaxalone, dantrolene, mephenesin, carisoprodol, 
methocarbamol, meprobamate, chlorzoxazone and chlormezanone  
 GABAergic drugs:  Progabide, gabapentin 
 Others (as identified by blinded data review) 
 
6.2.3 Dietary Restrictions 
An effort will be made to minimize variability of spasticity by advising stable caffeine and nicotine 
consumption, minimization of alcohol consumption, timing of study medication, and permitted 
prescription medication during the study period.   
 
6.3 Procedure(s) for Monitoring Subject Compliance 
Study medication will be dispensed by the site personnel.  This will be documented in the eCRF.  
Thus, it is expected that compliance will be accurately documented for each subject.  
 
Treatment compliance will be measured on the basis of a capsule count by the Investigator or 
designee for Visits 2 through 11.  Subjects will be instructed to bring the study medication (with the 
capsules that remain) with him/her at the next scheduled visit.  If the subject fails to bring the study 
medication on the designated day, he/she will be told to bring the same within the next 3 days, 
failing which it will be recorded as not available.   
 
6.4 Accountability Procedures for the Investigational Product 
A distributor will ship the medication to the study sites according to country specific laws and 
regulations, and the procedures will be described in Study Drug Accountability Document.  Both 
the distributor and the Investigator must keep record of all drugs received, used, and returned.  
When the study is completed, all unused investigational products must be returned to the Sponsor 
unless the Sponsor has approved other arrangements.  Any destruction of investigational products 
must be performed in accordance with the documented approved procedure from the Sponsor.  
 
At the completion of the study, there will be a final accountability of drug received, drug used, and 
drug returned/destroyed.  This reconciliation will be logged on the cumulative drug accountability 
form, signed and dated.  Any discrepancies must be investigated, resolved, and documented prior to 
return or destruction of unused study drug. 


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6.5 Maintenance of Study Treatment Randomization Codes and Procedures for 
Breaking Codes 
The randomization codes and blinding codes will be maintained by the statistician at the 
IVRS/IWRS.  The randomization numbers and blinding codes generated will not be disclosed to 
any individual associated with reviewing the study documents. 
 
 
The IVRS/IWRS will hold the only set of treatment codes and unblind individual subjects as 
required for regulatory reporting purposes.  However, the Investigator, Sponsor, and study team will 
be kept blinded to treatment allocation.  The treatment codes will be stored in a secure environment 
within the IVRS/IWRS and accessible only to the statistician.  
 
The treatment code may be broken on an individual basis, in case of an SAE for which the 
Investigator must know the study agent identity to initiate appropriate treatment.  The Investigator 
will be supplied with necessary information to break the study blind on an individual subject basis.  
If the study blind is broken, the Investigator must inform the medical monitor or designee and report 
the reason for unblinding.  Date, time, and reason, together with the Investigator‟s signature, must 
be recorded.  The site will contact the designated personnel from the IVRS/IWRS in case the 
treatment code needs to be broken.  
 
 
 
 
  
 
 
 
7 WITHDRAWAL AND REPLACEMENT RULES 
7.1 Withdrawal 
7.1.1 Premature Discontinuation of Subject in the Study 
The Investigator will make every effort to keep each subject in the study.  However, should a 
subject be removed from the study or elect to decline further study participation, the information 
will be recorded on the appropriate page (Final Status) in the eCRF and the 
 
  
 
 
 
 
 
 
As far as possible, all examinations scheduled for the final study visit must be performed on all 
subjects who receive study drug but do not complete the study according to protocol.   
 
The subject must return all unused investigational products.   


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Subjects who are withdrawn from the study due to AE will be treated according to established 
acceptable medical practice and followed for outcome.  All pertinent information concerning the 
outcome of such treatment will be entered in the eCRF. 
 
The Investigator will make every effort to contact subjects lost to follow-up.   
 
7.1.2 Early Stopping of the Study 
SPARC Ltd. may discontinue the study at any time, for ethical or scientific reasons.  The Investigator is 
entitled at any time to stop his or her participation in the study due to medical reasons.  In such a case, 
he/she should consult SPARC Ltd. at the earliest opportunity
.  
 
If the study is prematurely terminated or suspended, the IRB/IEC and the regulatory authorities will be 
informed promptly and provided with the reasons for the termination or suspension by the Investigator 
and SPARC Ltd., respectively
. 
 
7.2 Replacement 
Data from all enrolled subjects will be reported as outlined in Section 10.3.  Specifically, the same 
subject number will not be re-allotted if a subject withdraws from the study.   
 
8 ASSESMENT OF EFFICACY AND PHARMACOKINETICS 
8.1 Description of Efficacy Parameters  
Several measures are necessary to complete a thorough 
 
  
 
  
 
 
 
8.1.1 Primary Efficacy Parameter(s) 
8.1.1.1 Modified Ashworth Score 
The first and best known scale for measuring the degree of spasticity was the Ashworth scale, first 
developed in 1964 for use in a multiple sclerosis therapeutic trial.  Spasticity accounts for much of 
the disability affecting lower limbs.  Modified Ashworth score for the 12 movements of the lower 
extremities that will be measured will be evaluated as one of the primary efficacy parameters.  The 
Ashworth assessment is the current standard for clinical assessment of lower extremity spasticity 
and the most commonly used tool to evaluate the efficacy of pharmacologic and rehabilitation 
interventions for treatment of spasticity. 
 
At each scheduled visit for 
 
 
 
  
 


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The 6-point modified Ashworth scale scores are presented below: 
 
Score : Degree of Muscle Tone 
0 : No increase in tone 
1 : Slight increase in muscle tone, manifested by a catch, followed by minimal resistance at the 
end of the range of movement 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 remainder (less than half) of the range of movement 
2 : More marked increase in muscle tone through most of the range of movement, but affected 
part(s) easily moved 
3 : Considerable increase in muscle tone, passive movement difficult 
4 : Affected part(s) rigid in flexion or extension 
*note:  A change from 1 to 1+ and from 1+ to 2 will each be counted as a 1-point change 
 
8.1.1.2 Clinical Global Impression of Change (CGIC) 
CGIC will be assessed at Visits 4, 7, 8, 9, 10 and 11.  
 
 
 as indicated below:   
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 : 
 
  
 
  
 
  
 
  
 
   
 




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8.2 Methods and Timing for Assessing and Recording Efficacy Parameters 
Spasticity will be assessed at every visit using the 
.  Assessment at Visits 2 
through Visit 11 will be performed in the clinic.  The subject and his/her caregiver will be instructed 
about visit schedules
 
  
 
.  Throughout the study during both the 
fixed dose phase (Part 2) and 4-week double blind phase (Part 3) assessments are to occur   
 
.   
 
Assessors in the study team (doctors/ physiotherapists/ occupational therapists/ nurses across 
primary and secondary care) at all sites will be trained on scoring to achieve uniformity in 
assessments.  Attempts will be made to assign the same assessor  to an individual study subject for 
the duration of the study. 
Scores for each movement assessed will be recorded in the source documents and entered in the 
eCRF. Determination of treatment response and derivation of means and averages will be 
performed at the time of statistical analysis (see Section 10).  Statistical analysis of the efficacy 
parameters will be performed after data-lock according to the statistical analysis plan. 
 
8.3 
 
8.3.1 
 
 
 
  
 
 
 
. 
 
All blood samples will be collected 
  
.  The 
blood samples will be collected 
.  
 
 
 
 
 
 


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8.3.2 
 
8.3.2.1 
 
  
 
  
  
 
 
   
 
8.3.2.2  
 
 
 
 
 
8.3.3 
 
 
  
  
 
 
 
  
 
  
   
   
     
 
   
 
 
  
 
.  
 
9 ASSESSMENT OF SAFETY 
The Principal Investigator (PI), including the study staff, will monitor the subjects throughout the 
study period.  The staff will be available for subject queries during the regular business hours and 
via an answering service.  The PI or qualified medical designee will be on-site and/or available by 
cell phone throughout the study.  
 
9.1 Description of Safety Parameters 
The following safety parameters will be assessed during the study:   
 Treatment emergent adverse events 
 Daytime sedation  
 Vital Signs (seated blood pressure and pulse) 
 Clinical laboratory tests 
 12 Lead ECG 
 Physical examination  
 Neurological evaluation 


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 C-SSRS Suicidality Assessment 
 
9.1.1 Adverse Event 
An AE is any untoward medical occurrence during treatment with a pharmaceutical product in a 
subject that does not necessarily have a relationship with the treatment being administered.  An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product. 
 
Untoward medical experience occurring during medication-free pre-treatment periods does not meet 
the above-mentioned definition of an AE.  Nevertheless, they have to be documented in the same 
way as AE.  Each subject will be queried generally for the occurrence of adverse experiences prior 
to study drug administration and throughout the subject‟s participation in the study.  During and 
following a subject
's participation in this study, the Investigator has to ensure that adequate medical 
care is provided to a subject for any AE, including clinically significant laboratory values, related to 
the study.  The subject will be treated and/or followed up until the symptom(s) returns to normal or 
stabilizes, as judged by the PI. 
 
9.1.2 Serious Adverse Event 
A SAE or serious adverse drug reaction is any untoward medical occurrence that, at any dose: 
 Results in death 
 Is life-threatening 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
Or 
 Is a congenital anomaly/birth defect 
 
NOTE:  The term "life-threatening" in the definition of "serious" refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event, which, 
hypothetically, might have caused death if it were more severe. 
 
Medical and scientific judgment should be exercised in deciding whether expedited 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 
intervention to prevent one of the other outcomes listed in the definition above.  These should 
usually also be considered serious.  
 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse. 
 


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9.1.3 Pregnancy  
A urine pregnancy test will be performed at screening and subjects with a positive test will be 
excluded from study.  Women of child-bearing potential will be instructed to practice an acceptable 
method of birth control for the duration of the study.  A follow-up urine pregnancy screen will be 
conducted at Visit 7.  However, if subject becomes pregnant during the study, the pregnancy will be 
recorded as a significant medical event and procedure for expedited reporting (Section 9.2.1) will be 
followed.  The pregnancy will be followed until its outcome, and the outcome will be reported as a 
significant medical event and procedure for expedited reporting (Section 9.2.1) will be followed. 
 
9.2 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
9.2.1 Eliciting, Documentation and Reporting of Adverse Events and Intercurrent Illnesses 
Information on AEs will be derived by questioning the subjects in general terms (e.g., "How do you 
feel?” or “How have you been feeling since the last questioning?” respectively), by subjects
' 
spontaneous reports, or by observation. 
 
AEs will be documented on the source document.  The AE will be entered to the AE eCRF-pages. 
The following information will be given for each AE:  description of the AE, start date, stop date, 
severity, pattern (continuous/intermittent), action taken, outcome, seriousness, and causality 
assessment. 
 


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9.2.1.1 Rating of Adverse Events 
The following system will be used to assess causality as well as intensity of the AEs. 
TERM  
DEFINITION*  
CLARIFICATION 
Unrelated 
Those adverse events which, after careful consideration, are clearly due to extraneous causes (disease, 
environment, etc.) 
Unlikely  A clinical event, 
including laboratory 
test abnormality, with a 
temporal relationship to 
drug administration 
which makes a causal 
relationship 
improbable, and in 
which other drugs, 
chemicals or underlying 
disease provide 
plausible explanations. 
 
1. It does not follow a reasonable temporal  sequence (Improbable temporal 
relationship)  from  administration of the drug. 
 
2.  It could also be explained by patient
's concurrent disease, environmental 
factors, medical history and other concomitant drugs or chemicals including 
food-drug interactions 
 
Possibly  
A clinical event, 
including laboratory 
test abnormality, with a 
reasonable time 
sequence to  
administration of the 
drug, but which could 
also be explained by 
concurrent disease or 
other drugs or 
chemicals. Information 
on drug withdrawal 
may be lacking or 
unclear. 
 
1. It follows a reasonable temporal  sequence from  administration of the 
drug. 
 
2.  It could also be explained by patient
's concurrent disease, environmental 
factors, medical history and other concomitant drugs or chemicals 
(including food-drug interactions). 
 
3. There is no information or uncertainty with regard to what has happened 
after stopping the drug. 
 
Probably  A clinical event, 
including laboratory 
test abnormality, with a 
reasonable time 
sequence to 
administration of the 
drug, unlikely to be 
attributed to concurrent 
disease or other drugs 
or chemicals, and which 
follows a clinically 
reasonable response on 
withdrawal 
(dechallenge). 
Rechallenge 
information is not 
required to fulfil this 
definition. 
 
1. It follows a reasonable temporal  sequence from  administration of the 
drug. 
 
2. 
It could not be readily explained (unlikely) by the  patient
's concurrent 
disease, environmental factors, medical history and other concomitant 
drugs or chemicals including food-drug interactions. 
 
3. It disappears or decreases in severity on cessation or reduction in dose or 
on administration of a specific antagonist wherever possible. There are 
important exceptions when an adverse event does not disappear upon 
discontinuation of the drug, yet drug relatedness clearly exists. 
 
4. No rechallenge information is available or possible. 
 
Certain  
A clinical event, 
including laboratory 
test abnormality, 
 
1. It follows a plausible time sequence to drug intake ,this means that there 
is  a positive argument in sufficient detail to support the view that the drug 


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TERM  
DEFINITION*  
CLARIFICATION 
occurring in a plausible 
time relationship to  
drug administration, 
and which cannot be 
explained by concurrent 
disease or other drugs 
or chemicals. The 
response to withdrawal 
of the drug 
(dechallenge) should be 
clinically plausible. The 
event must be definitive 
pharmacologically or 
phenomenologically, 
using a satisfactory 
rechallenge procedure if 
necessary. 
is causally involved, pharmacologically or pathologically e.g. 
pharmacokinetics and type of reaction.  
2. It could not be explained by patient
's concurrent disease, environmental 
factors, medical history and other concomitant drugs or chemicals including 
food-drug interactions (i.e. no alternative causes). 
 
3. It disappears or decreases in severity on cessation or reduction in dose or 
on administration of a specific antagonist wherever possible. 
 
4. It is an objective and specific medical disorder or a recognized 
pharmacological phenomenon for instance „grey baby syndrome‟
 and 
chloramphenicol or anaphylaxis immediately after the administration of a 
drug that had been given previously. This means that any other event is 
automatically excluded and can never qualify for ‘Certain’ (even in the 
case of a positive rechallenge observation).  
 
5. It reappears on readministration of the drug (only if ethically correct i.e. 
in case of non-serious,  and easily treatable adverse events).  
 
 *http://www.who-umc.org/Graphics/24734.pdf  (as accessed on 19-Nov-2011). 
 
 
The severity of an adverse event is characterized as: 
 Mild: AE which is easily tolerated 
 Moderate: AE sufficiently discomforting to interfere with daily activity. 
 Severe:  AE, which prevents normal daily activities. 
 
9.2.1.2 Documentation and Reporting of Immediately Reportable Adverse Events 
Subject will be examined for any new medical conditions or worsening of the pre-existing ones.  
Any change in pre-existing conditions or new conditions must be entered on the AE page of the 
eCRF and any medication given on the concomitant medication pages. 
 
Any unexpected AE that could adversely affect the safety of the subjects or the conduct of the study 
and any SAE, which occurs during the course of this study, will be reported to the 
pharmacovigilance department of the CRO within 24 hours of the Investigator becoming aware of 
the event.  Any new information relating to an SAE that subsequently becomes available should 
also be faxed to the CRO Drug Safety within 24 hours of the Investigator becoming aware of the 
information.  
 
All SAEs must be reported, whether or not considered attributable to the study drug on a separate 
SAE Report Form according to the following procedures: 
 
As much information as possible should be supplied at the time of the initial report with at least the 
following information:  
 Name, address, and telephone number of the reporting Investigator 


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 Investigational product(s) 
 Protocol number 
 Subject identification number, initials, sex and date of birth 
 Description of the AE, reason considered serious, measures taken and outcome (if resolved) 
 Likelihood of drug causation of the adverse event assessed by the Investigator. 
 
 
 
   
 
 
 
  
 
 
   
 
 
 
  
 
  
 
 
 
 
 
 
  
 
9.2.1.3 Follow-Up of Subjects after Adverse Events (Serious and Non-Serious) 
Unresolved events and post-study events will be followed up by telephone or with unscheduled 
visits at the discretion of the Investigator.  These require evaluation and follow-up until the AE has 
been resolved or a reasonable explanation for its persistence is found. 
9.2.1.3.1 Unresolved Events 
If an AE/SAE is present when the subject has completed the main study period, the course of the 
event must be followed until final outcome is known. 
 
9.2.1.3.2 Post-study Events 
Any AE/SAE that occurs within 30 days after the end of the study should be reported.  Such events 
will be included in the safety analysis of the study.  
 
 
9.2.2 
 
  
 
 
 


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 following will be assessed:   
 
• 
 
 
 
 
 
 
 
 
    
 
9.2.3 Concomitant Medication and Physiotherapy Recording 
Medications used at study entry (and within the prior 30 days) will be recorded at Screening .  
Thereafter, concomitant medications used will be recorded at each visit.  At Screening , subjects 
will also be queried about their physiotherapy regimen and the nature and schedule recorded.  At 
subsequent visits, subjects will be questioned by the Ashworth assessor whether or not there has 
been a change; the nature of any substantive changes is to be described. 
9.2.4 Vital Sign Measurement 
Blood pressure and pulse will be measured at each clinic visit throughout study participation.  
Measurements will be made with the subject in a seated position (for at least 5 minutes).  Results 
will be evaluated against pre-specified criteria for clinically significant change.   
 
9.2.5 Clinical Laboratory Testing 
The following tests will be performed at Screening and Visit 7 (end of open-label fixed dose phase 
or upon early discontinuation): 
 
Hematology: 
 Red blood cell indices, including RBC count, hemoglobin, and hematocrit 
 Total WBC count 
 Differential WBC count 
 Platelet count 
 
Serum chemistry (Full Panel): 
 Sodium 
 Potassium 
 Chloride 
 CO2 
 Glucose (random) 
 BUN 
 Creatinine 
 Calcium 
 ALT 


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 AST 
 Alkaline phosphatase 
 Total bilirubin  
 Total protein 
 Albumin 
 
Urinalysis:  
 Dipstick for pH, specific gravity  
 Microscopic examination of the sediment  
 Urine pregnancy test (for women) to be performed at Screening, and Visit 7 (Week 18) and 
Visit 11 
 
Results for clinical laboratory parameters will be evaluated for clinically significant values 
according to pre-specified criteria.  Laboratory tests may also be repeated between scheduled visits 
at the discretion of the Investigator.  In addition, repeat testing should be performed at the end of the 
study to follow any clinically significant abnormality to resolution/stabilization. 
 
9.2.6 12-Lead ECG 
ECG measurements will be collected in triplicate 2 minutes apart (except at Screening where only 
one measurement will be taken) and read by a central reader.  The QTc data will be corrected using 
Fridericia‟s correction and Bazett‟s correction.  In addition to the QT interval, the following 
parameters will be collected:  PR interval, QRS, and ventricular rate; the presence of T-waves will 
be noted.   
 
Clinically significant abnormalities will be reported as AEs. 
 
9.2.7 Physical Examination 
Complete physical examination is to be performed at Screening and, as needed in response to 
changes in medical history, at the final study visit (Visit 11, or earlier in the event of premature 
termination).  The complete examination will consist of evaluation of the skin, head, eyes, ears, 
nose, throat, neck, thyroid, lungs, heart, lymph nodes, abdomen, and extremities.  Brief, targeted 
physical examinations are to be performed at other visits as necessary in response to clinically 
significant adverse events. 
 
9.2.8 Neurological Examination 
Neurological examination sufficient to establish the EDSS score is to be performed at Screening.  
The examination is to consist of an evaluation of mental status; corneal reflexes; extra-ocular 
movements; facial sensation (light touch); facial strength; palatal movement; tongue movements; 
neck extension; neck flexion; head turning; respiration; forced vital capacity; tendon reflexes of the 
right and left biceps, triceps, supinator, quadriceps, and ankle (scored as 0=absent, 1=reduced, 
2=normal, 3=increased, 4=clonus); and plantar stimulation (scored as 0=no movement or flexor; 
1=extensor).  Targeted examination is to be repeated, as needed in response to changes in medical 
history, at the final study visit (Visit 11, or earlier in the event of premature termination).   
 




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Approximately 300 subjects will be enrolled to ensure that at least 240 subjects are randomized at 
the beginning of Week 14 (Visit 7).  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.3 Study Populations 
10.3.1 Efficacy Populations  
10.3.1.1 ITT Population 
The ITT population will be defined as all subjects who are randomized to double-blind study drug at 
Visit 7 and subsequently received at least one dose of study medication.  
 
10.3.1.2 PP Population 
The per protocol (PP) population will be defined as all subjects who are randomized to double-blind 
study drug at Visit 7, subsequently receive at least one dose of study medication, have at least one 
on-treatment assessment in Part 3, and do not have any major protocol violation (such as poor 
compliance).  Protocol violations will be reviewed and subjects with major/minor violations will be 


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identified prior to unblinding the clinical database.  Subjects with a major protocol violation will be 
excluded from the analysis of the PP population. 
 
In addition, concomitant medications will be reviewed for anti-spasticity medication use, its dose, 
and the timing relative to the in-clinic assessment.  Adverse events will be reviewed in a similar 
fashion for confounding medical conditions.  In-clinic Ashworth assessments that are judged to be 
potentially confounded will be flagged.  The analysis of the PP population will exclude such 
potentially confounded assessments; response status will be solely on the basis of the clinician-rated 
CGIC. 
 
Analyses of the primary efficacy endpoint will be repeated using the PP population if it differs in 
size from the ITT population in total number by more than 10% overall.   
 
10.3.2 Safety Population 
The safety population will be all subjects who received at least one dose of 
 
 and have a subsequent contact.  Subjects who discontinue having received only   
 
and are not available for evaluation in Visit 2 or subjects dispensed  
 
 at Visit 2 but with no subsequent contact will not be included in the safety 
population.   
 
10.4 Statistical Methods 
A detailed statistical analysis plan (SAP) will be written and finalized before the study starts.  The 
plan will follow the outline of the statistical analyses including but not limited to points presented 
below, but details necessary to complete the statistical analyses will be given. 
 
10.4.1 Demographic and Other Baseline Characteristics 
Descriptive summaries of the Safety Population will be prepared for the demographic and baseline 
(Screening) characteristics listed below.  Categorical variables will be described with counts and 
percentages, ordinal variables with medians and quartiles, and interval variables with mean and 
95% confidence interval (CI).  
 
 
  Descriptive comparisons will be made using the Pearson‟s chi-square test for 
categorical variables, Mann-Whitney U-test for ordinal variables, and Student‟s two-sample t-test 
for interval variables. 
 
 Age (years) 
 Gender 
 Race/ethnicity 
 Renal function (as estimated by calculated creatinine clearance) 
 
 
  
 
  
 
 


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Medical history at Visit 1 (prior conditions and present conditions) will be tabulated by body 
system, both with a summary of incidence by diagnosis and the numbers and proportions with any 
abnormality.  A by subject listing will be created.   
 
10.4.2 Study Disposition and Dosing 
The following descriptive summaries of study disposition and dosing will be provided.  
 
10.4.2.1 Subject Disposition Criteria  
 Number of subjects who were enrolled in each phase of the study 
 
 Number and proportion of subjects (by treatment group and overall) who discontinued the 
double-blind phase prior to Visit 11. 
 Number and proportion of subjects (by treatment group and overall) who dropped-out for 
each of the following categories for why a subject may be prematurely discontinued from 
the study (Section 7.1.1):   
 
o Dropped-Out Due to Adverse Event:  Subjects who are discontinued from the study 
medication due to the occurrence of an AE will be recorded as dropouts.  The AE will be 
recorded and all subjects irrespective of time of dropout (after Visit 2 and have taken one 
study dose) will be considered for safety analysis.  
 
o Dropped-Out Due to Major Protocol Violation:  Subjects who are discontinued from the 
study due to the occurrence of a major protocol violation will be recorded as dropouts.  
The protocol violation will be recorded and all subjects irrespective of time of dropout 
(after Visit 2 and have taken one study dose) will be considered for safety analysis.  
 
o Lost to Follow-Up:  Subjects available for evaluation in Visit 2 
 
, but not evaluated for subsequent visits will be considered 
as lost to follow-up, 
 will be 
considered for safety analysis.  
 
o 
 
 
 
 
 
 
o Dropped Due to Other Reasons:  Subjects who are discontinued from the study due to 
any other reason will be recorded as dropouts.  The reason for discontinuation will be 
recorded all subjects irrespective of time of dropout (after Visit 2 and have taken one 
study dose) will be considered for safety analysis.   
 
Subjects who drop out after Visit 1 will not be replaced (Section 7.2).  
 


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10.4.2.2 Dosing 
Dosing data at each visit will be summarized.  Specifically
, the numbers of subjects for each dose 
level and descriptive summaries (mean, median, and standard deviation) of dose at each visit will be 
provided.  Individual subject listings will be prepared.  
 
 
 
   
 
10.4.3 Efficacy Analysis 
10.4.3.1 Primary Efficacy Analysis 
The primary efficacy analysis will be performed using the intent-to-treat (ITT) population.   
  
A
 subject will be classified as „
treatment failure‟
 if the definition for failure (Section 10.1) is met at 
any time during the double-blind withdrawal period (Part 3).  
 
 
.  The 
primary efficacy analysis will be carried out using a two-sided test at the alpha=0.05 level of 
significance. 
 
10.4.3.2 Additional Analyses of the Primary Efficacy Outcome 
10.4.3.2.1 Sensitivity Analyses 
Several sensitivity analyses 
 
 
 
 
 
 
 
  The sensitivity analyses are as follows: 
 
(a) 
. 
 
(b) 
 
 
 
(c) 
 
   
 
(d) 
 
 
 
 




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10.4.3.4.2 Subgroup Analyses 
Exploratory subgroup analyses will be performed to investigate the effect of the drug for different 
subgroups, 
 
 those who used neurological concomitant medications 
versus those that did not use such medications, and initial severity based on modified Ashworth 
score.   
 
10.4.3.4.3 Sleep Interference Due to Spasticity   
10.4.3.4.3.1 Awakenings Due to Spasticity 
 
 
 
   
 
 
 
 
.   
 
 
 
 
. 
 
10.4.3.4.3.2 Hours of Sleep 
 
 
 
   
 
 
 
 
   
 
10.4.3.4.4 Spasm Frequency  
 
   
 
 
 
el.   


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The weekly mean of the daily spasm frequency will be computed using the average of the daily 
results that are obtained during the specified 7-day period.  However, the weekly mean will be set to 
a missing value if a subject provides fewer than 3 days of data during the week. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.   
 
10.4.5 Safety Analysis 
Safety parameters include AEs, daytime sedation, vital signs (resting pulse and sitting systolic and 
diastolic blood pressures), clinical laboratory tests, 12 lead ECG
, physical examinations, 
neurological examinations and suicidality assessment. 
 
 
  
 
. 
10.4.5.1 Adverse Events  
All treatment-emergent adverse events (TEAE) will be coded in a standardized manner for 
regulatory activities.  TEAEs will be coded according to body systems and preferred terms.  A 


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TEAE is defined as any event that only occurred after 
 administration 
or that existed before drug administration but increased in severity or treatment attribution.  For the 
randomized withdrawal phase, emergent events will be determined relative to the double-blind 
medication. 
 
Adverse events reported as pre-existing at the start of the run-in  
 or that emerge during 
the
treatment phase will be considered pre-treatment adverse events.  These will be 
summarized separately. 
 
The incidence of TEAEs and SAEs will be summarized for the 
 
s (Part 2) and also by treatment group during the double-blind, 
part 
(Part 3).  For each part, the incidence of TEAEs will be presented by system organ classification 
and preferred terms according to the Medical Dictionary for Regulatory Activities (MedDRA®), by 
causality, by severity, and by action taken.  In addition, separate summaries will be prepared with 
subjects categorized by sex, age (below 65 years of age and 65 years of age and older), and race. 
 
The effects of concomitant medications and/or medical conditions present at screening will also be 
explored.  Should any medications be used by or conditions be present in 20% or more of the 
subjects overall, subjects will be categorized accordingly and the incidence of TEAEs in each part 
summarized.  Additional drugs or diagnoses of interest may be identified during the blinded data 
review. 
 
In addition, adverse events will be listed for all subjects, including verbatim and coded terms. 
10.4.5.2 
 
  
    
 
 
 
   
 
   
 
 
 
 
.   
10.4.5.3 Vital Signs  
Sitting diastolic and systolic blood pressures and resting pulse measurements at each visit will be 
summarized using descriptive statistics (n, mean, standard deviation, median, minimum, and 
maximum) for measurements during the open-label phase and also by treatment groups during the 
randomized double-blind withdrawal phase.  Similarly, change from Visit 1 at each visit will be 
summarized using descriptive statistics. 
 
Values considered clinically significant by the Investigator are to be flagged.  Criteria for possibly 
significant changes will be established a priori.  Number and percentages of subjects with values of 




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findings will be listed.  These will be reviewed for any emergent abnormalities that could be 
attributed to the new dosage form.  
 
 
 
 
 
 
 
 
. 
 
10.4.6 Prior and Concomitant Medications  
Prior and concomitant medications will be coded using WHODRUG and will be summarized using 
counts and percentages.  
 
Neurological and anti-spasticity concomitant medications will be summarized separately for each 
treatment group using counts and percentages and will be listed for all subjects. 
 
All recently used (within 30 days prior to Screening) concomitant medications will be listed for all 
subjects. 
 
10.5 Unblinding 
Breaking of the blind will occur at completion of the study.     
 
At completion of the study, breaking of the blind will occur once the database has been cleaned and 
locked.  Prior to final database lock, any major protocol violations, including changes in medication 
use or physiotherapy, and changes in medical condition will be identified.  Only at that time will the 
Sponsor be granted access to the unblinded data.   
 
At all other timepoints, breaking of the blind for any subject is discouraged and should be 
performed only under medical emergency conditions where the identification of the subject‟s
 
treatment assignment is critical for proper medical care to be administered.  In such circumstances, 
the Investigator must contact the Sponsor‟s Medical Representative (or designee) for permission to 
unblind.  The representative will be available 24 hours a day.  If a decision is made to unblind a 
subject
's assignment, the Investigator will call the IVRS/IWRS statistician and request the subject
's 
treatment group.  Only the Investigator and the IVRS/IWRS statistician will be unblinded to the 
subject
's treatment group and they will be responsible for documenting the time, date, and reason 
for code break. 
10.6 Level of Significance 
All statistical tests will be carried out at the alpha=0.05 level of significance. 
 


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10.7 Missing Data 
Every effort will be made to collect all the data and avoid missing data.  For intention–to-treat (ITT) 
efficacy data, multiple sensitivity analyses will be completed. 
 
All missing values will be queried and resolved to the best possible extent. 
 
10.8 Procedures for Reporting Protocol Violations/Deviations 
Before starting the study, a list of major protocol violations that justify exclusion of subjects from 
efficacy analysis will be made. Likewise, a list of minor protocol violations/deviations that are 
tolerable for retaining the subject in the study will be made. 
 
Subjects excluded for analysis for major protocol violations will be listed along with the nature of 
the violation. Subjects having minor protocol violations/deviations will be listed. 
 
11 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1 Monitoring 
On-site monitoring will be performed before, during, and after the study. The monitor will ensure 
that the study is conducted, recorded and reported in accordance with the protocol, SOPs, GCP, and 
the applicable regulatory requirements.  The monitor will check the accuracy and completeness of 
the eCRF entries, source documents, and other study-related records against each other.  The 
Investigator will provide direct access to source data/documents for study-related monitoring.  It is 
important that the Investigator and/or other staff are available at these visits.  The Investigator 
should maintain source documents such as laboratory reports, history and physical examination 
reports, etc., for possible review.   
 
The monitor will follow written SOPs as well as those procedures that are specified by the CRO for 
monitoring a specific study.  The monitor will record the date of each visit together with a summary 
of the status and progress of the study.  Proposed actions will be confirmed with the Investigator in 
writing. 
 
11.2 Documentation at the Study Site 
All data relating to the study will be documented in the eCRF. This eCRF is developed to record the 
data requested by the protocol.  The Investigator will ensure the accuracy, completeness, legibility, 
and timeliness of the data recorded in the eCRFs.  Any change or correction to an eCRF will be 
dated, initialed, and explained (if necessary) and will not obscure the original entry. 
 
At the beginning of the study, a site master file will be established at the investigational site.  The 
Investigator will maintain the study documents as specified in the ICH Guideline of GCP and as 
required by the applicable regulatory requirements.  The Investigator will take measures to prevent 
accidental or premature destruction of these documents. 
 


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Prior to the start of the study, a signature and delegation list will be completed showing the 
signatures and hand-written initials of all who are authorized to entry data or make corrections in 
the eCRF. 
 
The Investigator will permit study-related monitoring, audits, and regulatory inspection, providing 
direct access to source data/documents. 
11.3 Subject's Data and Data Protection 
To protect the subject
's identity, subject initials and a subject number will be assigned by the 
Investigator to each study subject and used in lieu of the subject
's name when the Investigator 
reports AEs and/or other study-related data.  Personal information will be treated as confidential but 
may need to be reviewed by authorized representatives of the CRO (monitor and auditor) and 
regulatory authorities.  The subject
's consent for direct access to his original medical records for 
data verification purposes has to be obtained prior to a subject
's participation in the study. 
 
The Investigator must maintain a list of names and identifying information (e.g., initials, date of 
birth, subject identification code and date of study randomization) of all subjects enrolled in the 
study.  The Investigator will keep the subject identification code list in the site master file. 
 
11.4 Data Management and Analysis  
Data management based on GCP refers to the activities defined for achieving routines for entering 
subject information in a database in an efficient and error-free manner.  
 
Data management routines include procedures for handling the eCRFs, database set up and 
handling, data verification, data validation, database quality control (QC), and documentation of 
activities performed, including information on discrepancies in the procedure.  
 
Data Manager and Biostatistician from the CRO will perform the data management and analysis.  
 
The initial notification of SAEs will be entered into the CROs safety database for coding, medical 
evaluation, and notification to the Health Authorities according to national regulatory requirements.  
Before clean-file, reconciliation will be performed between the two databases for all SAEs. 
 
All data will be entered into the Oracle Clinical RDC system by site personnel.  All data will 
undergo 100% source verification at the interim site visits by the monitor.  In addition all data will 
undergo electronic edit checks and validation.  Discrepant data will require resolution by the site 
personnel.  The data will require Principal Investigator electronic signature at predetermined time 
points and at the end of each study book.  When the data for a subject is declared clean (all data 
entered, verified, validated and resolved) the case book will be frozen.  At the close of the study, 
after all data has been transmitted to the statistician for final analysis; the sponsor will authorize 
final database lock. 
 
The QC of data will be performed to ensure that data entry and verification have been performed 
correctly in accordance to predefined instructions.  
 


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When the data have been entered, verified, and validated, the database will be locked for the 
analysis to start (Clean File).  
 
11.5 Amendments to the Protocol 
The Investigator will not implement any deviation from, or changes to the protocol without agreement 
by Sponsor and prior review and documented approval/favorable opinion from the IRB/IEC of an 
amendment, except where necessary to eliminate immediate hazards to study subject or when the 
changes involve only logistical or administrative aspects of the study (e.g., change in monitor(s), 
change in telephone numbers).  
 
All changes or deviations of the trial must be confirmed in writing.  Changes resulting in 
amendments will be made jointly between the CRO, the Sponsor and Investigator(s). 
Amendment(s) will be signed off in the same way as the protocol.  
 
11.5.1 Emergencies 
When an emergency occurs that requires a departure from the protocol for an individual, a departure 
will be only for that subject.  The Investigator or other physician in attendance in such an 
emergency will, if circumstances and time permit, contact the following person immediately by 
telephone at: 
 
  
 
 
 
 
 
 
 
 
Such contacts will be made as soon as possible to permit a decision as to whether or not the subject 
(for whom the departure from protocol was affected) is to continue in the study.  The eCRFs will 
completely describe the departure from the protocol and state the reasons for such departure.  In 
addition, the IRB/ IEC will be notified in writing of such departure from protocol. 
 
11.5.2 Protocol Violations/ Deviations 
Protocol violations may be defined as divergences from the inclusion and exclusion criteria, 
concomitant medication restrictions, and any other protocol requirement that results in a significant 
added risk to the subject or has an impact on the quality of the data collected or the outcome of the 
study.  A subject may, but is not required, to be withdrawn if it is discovered that he/she committed 
a protocol violation during the course of the study.   
 
A protocol deviation may be defined as an occurrence when there is non-adherence to study 
procedures or schedules as specified by the protocol that does not involve inclusion/ exclusion 
criteria or the primary endpoint and that does not place the subject at any added risk or affect the 
data quality or study outcome.  Examples of “deviations” may include common out-of-window 
visits, a missed procedure, etc.  A subject may not have to withdraw if the deviation is discovered 
during the course of the study; this decision will be made by the Investigator in conjunction with the 
Sponsor.  
 


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Protocol violations and deviations will be recorded on the appropriate eCRF page and tracked in a 
protocol violation and deviation log.  The Medical monitor and Sponsor (or designee) should also 
be made aware of all protocol violations.  Protocol violations and deviations must be reported in the 
final clinical study report.  
 
12 QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator and the study monitor (or designee) are to ensure that the study staff receives 
appropriate training and that any information relevant to the conduct of this study is forwarded to other 
staff as appropriate.  
 
Quality assurance and quality control systems are implemented and maintained using written SOPs to 
ensure that the study is conducted and data are generated, documented (recorded), and reported in 
compliance with the protocol, GCP, and the applicable regulatory requirement(s).  
 
Quality control will be applied to each stage of data handling to ensure that all data are reliable and 
have been processed correctly.  
 
Sponsor or designee at the end of the study may conduct an internal or external audit.  In such an 
instance, the auditor will be allowed direct access to the source medical records, the eCRFs, and the 
Site‟s master file for the study.  
 
13 ETHICS 
Before initiation of the study, Sponsor will seek permission from the regulatory authorities for 
conducting the study.  All documents required by the appropriate authorities will be submitted.  Any 
notification/submission will be dated and contain sufficient information to identify the protocol. 
 
13.1 Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
This study will be initiated after the protocol is reviewed and approved by the concerned IRB/IEC.  
The approval should be kept on file in the site master file with a copy in the Sponsor‟s file at the 
CRO. 
 
13.2 Ethical Conduct of the Study 
This study will be carried out in conformity with GCP described in Guideline E6 of the ICH.  This 
study will also be carried out in conformity with the laws, rules, and regulations prevailing in the 
state and country of the investigational site. 
 
13.3 Subject Information and Consent 
Subject will be screened and included in the study only after giving them adequate and appropriate 
information, and obtaining a written informed consent.  The subject will be given sufficient time to 
consider the study‟s 
implications before deciding to participate.  The subject will be provided with a 


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copy of the signed informed consent form.  The confidentiality of the subject‟s records will be 
maintained. 
 
Should there be any amendments to the Final Protocol, such that would directly affect the subject‟s 
participation in the study, e.g., a change in any procedure, the ICF will be amended to incorporate 
this modification and the subject must agree to sign this amended form indicating that they re-
consent to continue their participation in the study.  
 
The Investigator is responsible for obtaining the subject‟s freely given written consent, including 
date, and thereafter sign and date the consent form by her/himself before any study related 
procedure is performed. 
 
14 DATA HANDLING AND RECORD KEEPING 
The Investigator must maintain all documentation relating to this study.  Essential documents (as 
defined in the ICH Guideline of GCP) must be retained until at least 5 years after the last approval of a 
marketing application in an ICH region, and until there are no pending or contemplated marketing 
applications in an ICH region or at least 5 years have elapsed since the formal discontinuation of 
clinical development of the investigational product.  These documents must be retained for a longer 
period, however, if required by the applicable regulatory requirement(s) or if needed by Sponsor.  
 
In any case, all study records such as but not limited to eCRFs, regulatory documents, the subject 
identification code list, subject files and other source data that support eCRFs must be retained for at 
least 15-years after the completion or discontinuation of the study.  If the Investigator retires, relocates 
or for other reasons withdraws from the responsibility of keeping the study records, custody must be 
transferred and Sponsor notified in writing. 
 
Sponsor will notify the Investigator in writing when the study-related records are no longer needed. 
 
15 FINANCING AND INSURANCE 
The Sponsor is covered by a liability insurance that also covers liability towards subjects in clinical 
trials. Sponsor is covered by a General and Products liability insurance that includes clinical trials. 
 
16 PUBLICATION POLICY 
The CRO and Investigator agree to keep strictly confidential all unpublished information and results 
concerning this study.  Unpublished information must not be published or disclosed without 
Sponsor‟s prior written approval.  Sponsor reserves all the rights to declare any of its data confidential 
or of business importance and will provide it only to the regulatory authorities of concern on 
request/demand. 
 
Publications except for summaries of product characteristics are subject to the written consent of the 
other party of the contract, which shall not unduly be refused.  

SAP_001.pdf: 
Statistical analysis plan Verison 9.0, 21 Sep 2017
Title of the study: A placebo-controlled randomized withdrawal evaluation of the efficacy and safety 
of Baclofen ER capsules (GRS) in  subjects with spasticity due to multiple sclerosis
NCT number: NCT01457352


Statistical Analysis Plan 
Study Title: 
A Placebo-Controlled Randomized Withdrawal Evaluation of the 
Efficacy and Safety of 
 in Subjects with 
Spasticity Due to Multiple Sclerosis 
Protocol Number: 
Amendment  
CLR_09_21 
Version 07 Amendment 04 16 Dec 2016 
Sponsor: 
Sun Pharma Advanced Research Company Ltd., 
Sponsor Contact: 
CRO: 
Version No./Date 
Version 9.0 / 21Sep2017 
Confidential Statement: This protocol is a confidential document owned by Sun Pharma Advanced 
Research Company Ltd., India (SPARC Ltd.).  Any unpublished information contained in it may not be 
disclosed to a third party without prior written approval of SPARC Ltd., India.  However, the document may be 
disclosed to an Institutional Review Board, an Independent Ethics Committee or a statutory regulatory authority 
under a similar condition of confidentiality. 


Sun Pharma Advanced Research Company, Ltd. 
Protocol CLR_09_21 
Statistical Analysis Plan 
 
 
Version 9.0 
 
 
 
21Sep2017 
 
 
 
 
Page 2 of 53 
Confidential 
 
Signatory Page 
 
This Statistical Analysis Plan was reviewed and approved by: 
 
 
 


Sun Pharma Advanced Research Company, Ltd. 
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REVISION HISTORY 
 


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TABLE OF CONTENTS  
 
Signatory Page ............................................................................................................................ 2 
1. 
List of abbreviations and acronyms ................................................................................ 7 
2. 
Introduction ....................................................................................................................... 9 
3. 
Study Overview ............................................................................................................... 10 
3.1 
Study Objectives .................................................................................................. 10 
3.1.1 
Primary Objectives .............................................................................. 10 
3.1.2 
Secondary Objectives .......................................................................... 10 
3.1.3 
Exoploratory Objectives ...................................................................... 10 
3.2 
Study Design ........................................................................................................ 10 
3.2.1 
Sample Size Considerations ................................................................ 12 
3.2.2 
Randomization ..................................................................................... 13 
3.2.3 
Study Assessments Schedules .............................................................. 15 
4. 
Study Endpoints and Definitions ................................................................................... 18 
4.1 
Primary Efficacy Endpoint ................................................................................ 18 
4.2 
Secondary Efficacy Endpoints ........................................................................... 18 
4.3 
Additional Efficacy Endpoints ........................................................................... 18 
4.4 
Exploratory Endpoints ....................................................................................... 18 
4.5 
Safety Endpoints .................................................................................................. 19 
4.6 
Study Definitions ................................................................................................. 19 
4.6.1 
Study Day ............................................................................................ 19 
4.6.2 
Baseline and Change from Baseline ................................................... 20 
5. 
Statistical Analysis General Considerations ................................................................. 20 
5.1 
Analysis Populations ........................................................................................... 20 
5.2 
P-Values................................................................................................................ 21 
5.3 
Procedures for Handling Missing Data and Outliers ...................................... 21 
5.4 
Interim Analysis .................................................................................................. 21 
5.5 
Blinded Review of Data....................................................................................... 21 
5.6 
Final Reporting and Analysis ............................................................................. 22 
5.7 
Multi-center Studies ............................................................................................ 22 
6. 
Statistical Analysis Methodology ................................................................................... 23 
6.1 
Study Subjects ..................................................................................................... 23 
6.1.1 
Subject Disposition .............................................................................. 23 
6.1.2 
Demographics ..................................................................................... 24 
6.1.3 
Protocol Deviations............................................................................. 24 


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6.1.4 
Medical and Surgical History ............................................................. 25 
6.1.5 
Multiple Sclerosis History ................................................................... 25 
6.1.6 
Spasticity History ................................................................................ 25 
6.1.7 
Concomitant Medications ................................................................... 25 
6.1.8 
Exposure and Compliance .................................................................. 27 
6.2 
Efficacy Analysis ................................................................................................. 28 
6.2.1 
Primary Efficacy Analysis ................................................................... 28 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.2 
Secondary Efficacy Analyses ............................................................... 30 
 
 
 
 
6.2.3 
Additional Efficacy Analyses ............................................................... 31 
6.2.4 
Exploratory Efficacy Analyses ............................................................ 32 
 
 
 
 
 
 
 
 
 
 
 
6.2.5 
 
6.3 
Safety Analysis ..................................................................................................... 36 
6.3.1 
Adverse Events .................................................................................... 36 
6.3.2 
Clinical Laboratory Tests ................................................................... 38 
6.3.3 
Vital Signs ........................................................................................... 40 
6.3.4 
12-Lead ECG....................................................................................... 41 
6.3.5 
Physical Exam ..................................................................................... 41 
6.3.6 
Neurological Examinations ................................................................. 42 
6.3.7 
Suicidality Assessments using C-SSRS ................................................ 42 
7. 
Testing/Quality Control Plan and Software/System .................................................... 44 
7.1 
Programming Specifications for TFLs .............................................................. 44 
7.2 
Formatting Conventions ..................................................................................... 44 
7.3 
Standard Text Conventions ................................................................................ 45 
7.3.1 
Header ................................................................................................. 45 
7.3.2 
Title...................................................................................................... 45 
7.3.3 
Footnotes ............................................................................................. 45 
7.3.4 
Footer .................................................................................................. 46 
7.4 
Statistical Conventions ........................................................................................ 46 
7.4.1 
Statistics Reported ............................................................................... 46 


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7.4.2 
SAS Procedure Output ........................................................................ 47 
7.4.3 
Tables Summarizing Categorical Data ............................................... 47 
7.4.4 
Subject Data Listings .......................................................................... 47 
8. 
References ........................................................................................................................ 48 
9. 
Appendices ....................................................................................................................... 49 
9.1 
Planned Tables, Listings, and Figures ............................................................... 49 
 
 
 


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1. LIST OF ABBREVIATIONS AND ACRONYMS 
AE                            Adverse Event 
ALT (SGPT)            Alanine aminotransferase (Serum Glutamate Pyruvic Transaminase)  
ANCOVA                 Analysis of Covariance 
AST (SGOT)            Aspartate aminotransferase (Serum Glutamate Oxaloacetate Transaminase)
BUN 
C-CASA 
Blood Urea Nitrogen 
Columbia Classification Algorithm of Suicide Assessment
CGIC                        Clinician Global Impression of Change 
CI                             Confidence Interval 
CMH                          Cochran Mantel-Haenszel 
CRO                         Contact Research Organization
CSR 
C-SSRS 
Clinical Study Report 
Columbia – Suicide Severity Rating Scale
ECG                         Electrocardiogram 
eCRF                        electronic Case Record Form/ electronic Case Report Form 
EDSS                       Expanded Disability Status Scale  
e.g.                           For example 
                            
 
                          
 
                             
 
ITT                           Intent-To-Treat 
IVRS                        Interactive Voice Response System 
IWRS                       Interactive Web Response System 
MedDRA                  Medical Dictionary for Regulatory Activities 
mg                            Milligram
mL  
 
Milliliter 
MS                            Multiple Sclerosis 
SGIS                         Subject Global Impression of Severity 
PP                             Per Protocol 
SAE                          Serious Adverse Event 
SAP                          Statistical Analysis Plan 
SD                            Standard Deviation 
SPARC Ltd.             Sun Pharma Advanced Research Company Limited 
TEAE                       Treatment Emergent Adverse Event 
 
 


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ULN  
VAS 
  WBC 
 
 
Upper Limit of Normal 
Visual Analogue Scale 
White Blood Cell


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2. INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned statistical analyses to be 
performed for the analysis of data from Study CLR_09_21, “A Placebo-Controlled 
Randomized Withdrawal Evaluation of the Efficacy and Safety of 
 
 in Subjects with Spasticity Due to Multiple Sclerosis.” 
The SAP is prepared to provide a more technical and detailed elaboration of the principal 
statistical features stated in the protocol. The SAP will ensure that the tables, listings, and 
figures that will be produced and statistical methods that will be used are complete and 
accurate and will allow valid conclusions to be drawn. In the development of this SAP, the 
following documents were used: 
• Protocol Number Version 7.0 Amendent 04,  16 Dec 2016 
• Electronic Case Report Form (eCRF), 09 Mar 2012 
 
The principles in the following guidance documents are followed in preparation of this SAP: 
• International Conference on Harmonisation (ICH) E3 (1995): Structure and 
Content of Clinical Study Reports 
• ICH E6 (1996): Guideline for Good Clinical Practice 
• ICH E9 (1998): Statistical Principles for Clinical Trials 
In the event that a discrepancy is found between the descriptions in the statistical section of 
the protocol and this document, the description in this document supersedes the descriptions 
in the statistical section of the protocol. 
 
 The responsible party at SPARC Ltd. will be required to 
review and approve all versions of the SAP. 
 
 


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3. STUDY OVERVIEW 
3.1 Study Objectives 
3.1.1 Primary Objectives 
The primary objectives are to compare the continued treatment 
 
 versus down-titration to placebo 
 
 
• Demonstrating efficacy of 
 in the treatment of 
spasticity 
• Indirectly demonstrating 
 
• Determining the safety profile 
 
3.1.2 Secondary Objectives  
To determine effects on another corollary measure of spasticity such as: 
• Subject’s assessment of spasticity severity 
3.1.3 Exoploratory Objectives 
 
 
 
 
 
 
 
 
 
 
3.2 Study Design 
The study is a 
 multicenter, out-patient trial in subjects 
with spasticity due to MS (Multiple Sclerosis).  The study will be performed in three 
parts: a 1-week open-label phase (Part 1)
 a 16-
week open-label phase (Part 2)
 
 and a 4-week, double-blind, placebo-controlled, 
randomized withdrawal phase (Part 3).  Subjects will be informed that at some time 
during the study, they may receive placebo, however, they will not be informed at which 
visit this will commence. An overview scheme of the study and the schedule of events are 
presented in Section 3.2.3. 
 
Approximately 300 subjects will be enrolled to ensure that at least 240 subjects are 
randomized in Part 3.  Subjects will be screened for eligibility within 14 days of the initial 
visit by medical history, recent and concomitant medication use, physical and 
neurological examination, 12-lead ECG, clinical laboratory testing, and assigned a subject 
number.  Following provision of informed consent and successful screening, eligible 


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subjects will be enrolled in the study (Visit 1). Once on study, subjects will be seen in the 
clinic at the end of the 7-day 
 (Visit 2), at which point they will be 
converted to 
. They will be seen in the clinic every 2 weeks 
 
 
 
 
 
. 
 subjects are to remain on a fixed dose 
for an additional 12 weeks;
 
 
 
 
At the beginning of Week 18 (Visit 7), subjects who have remained on a fixed dose of 
 for 12 to 16 weeks, without further need for adjustment in 
medication, will be randomly assigned to either remain on 
 
in the same dose or placebo for an additional 4 weeks.  
 
 
 
  
The final scheduled study visit is Visit 11, 
  
 
 
. 
 
 
 
. 
 
Subjects will be evaluated for efficacy as briefly described below.  The efficacy 
instruments and assessments are further described in Section 6.2. 
 
• 
 
 
  Right and left hip flexion and abduction, knee flexion and extension, 
and ankle dorsiflexion and plantar flexion will be assessed using the modified 
Ashworth Scale, 6-point version (inclusive of 1+), rated from 0 to 4, for a total 
of 12 movements being evaluated. This same individual will query the subject 
for any changes in physiotherapy regimen.  The modified Ashworth Scale 
assessment is further discussed in Section 6.2.1. 
• Clinician Global Impression of Change (CGIC) will be assessed by the Treating 
Physician, 
 


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 the CGIC will be assessed at Visits 4 and 7 
 
 and at Visits 8,9, 10 and 11 
 
 
• The Subject Global Impression of Severity (SGIS) 
 will be 
assessed atVisits 4, 7, 8, 9, 10, and 11. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
During the course of the study, subjects will be monitored for adverse events and vital 
signs (seated blood pressure, pulse, respiration, and body temperature) measured at each 
clinic visit. Suicidality will be assessed at every visit using the Columbia – Suicide 
Severity Rating Scale (C-SSRS).  Clinical laboratory testing will be repeated at the end of 
the open-label phase, 
 after all subjects have received a fixed-dose 
 
, and if needed, at Visit 11 (Week 22) 
or early termination.  ECGs will be recorded at screening, after subjects have completed 
the 
 run-in (Visit 2), after subjects have received 
 
for 6 weeks (Visit 4), after subjects have received 
 
 for 18 weeks (Visit 7), and if needed, at Week 22 (Visit 11) or early termination.  
Physical and neurological evaluation will be performed at screening and if needed, at 
Week 22 (Visit 11) or early termination. 
 
At the final visit
 clinical laboratory testing, 
ECG measurement, and physical and neurological evaluation will be performed if needed. 
Any treatment-emergent abnormalities shall continue to be evaluated with testing as 
needed to follow resolution. 
 
Subjects will be instructed that even though they may have extra medication, they should 
return to the clinic for their visits according to the schedule of events. 
 
Subjects who enter the double-blind randomized withdrawal phase (Part 3) will be offered 
the opportunity to participate in a separate open-label trial 
 
 
3.2.1 Sample Size Considerations  
 


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4. STUDY ENDPOINTS AND DEFINITIONS 
4.1 Primary Efficacy Endpoint 
The primary efficacy variable is the proportion of subjects who become a treatment failure 
during the double-blind randomized withdrawal part (Part 3). A subject’s response status will 
be determined after database lock, but prior to unblinding the data. A subject who meets the 
following criterion will be considered a treatment failure: 
• A CGIC of ≥ 5 (“minimally worse” to “very much worse”) and at least one 
movement with a ≥ 1 unit increase 1 in modified Ashworth score from Baseline 
Derivation of the primary endpoint is outlined in Section 6.2.1.3. 
4.2 Secondary Efficacy Endpoints 
• The secondary efficacy variable is the difference between treatment groups in 
Subject Global Impression of Severity (SGIS) scores at Visit 11. If Visit 11 is 
missing, the last available SGIS will be used.  
 
4.3 Additional Efficacy Endpoints 
 
 
 
 
 
 
 
 
 
4.4 Exploratory Endpoints 
Exploratory efficacy endpoints include: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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• 
 
 
 
 
 
 
 
 
 
 
 
4.5 Safety Endpoints 
• Adverse Events 
• Vital signs – resting pulse, sitting systolic and diastolic blood pressure, respiration, 
and body temperature 
• Clinical laboratory tests 
• 12 lead electrocardiogram (ECG) 
• Neurological examinations 
• Suicidality assessments 
• Exposure and compliance 
• 
 
• Physical examinations 
 
4.6 Study Definitions  
4.6.1 Study Day  
For purposes of describing days on study drug in data listings, data will be assigned a study 
day, relative to the start 
 at Visit 2, according to the following 
rules (this numbering of days differs from the Study Days as described in the protocol): 
For events that occurred after Visit 2: 
 
Study Day = visit date – date of Visit 2 + 1 
For events prior to Visit 2: 
 
Study Day = visit date – date of Visit 2 
Visit numbers as designated on the study eCRFs (Electronic Case Report Forms) will be 
used. For selected parameters, visit windows will also be calculated for use in descriptive 
statistics by time. 
 


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4.6.2 Baseline and Change from Baseline  
The baseline time point for different assessments will be defined in the respective sections. 
For evaluations that are collected at multiple occasions prior to initiation of study treatment, 
the latest evaluation will be considered the "Baseline" evaluation for analysis. 
Unless indicated otherwise, change from baseline (CFB) will be calculated as follows: 
• CFB = Value at Visit - Baseline 
 
5. STATISTICAL ANALYSIS GENERAL CONSIDERATIONS  
5.1 Analysis Populations  
Safety Population: 
The safety population will be all subjects who received at least one dose of 
 
.  Subjects who discontinue having received only 
 (in Part 1) and 
are not available for evaluation at Visit 2 will not be included in the safety population. The 
Safety Population for Part 3 will be based on only those Safety subjects who received a dose 
of randomized study drug at Visit 7.  
 
Intent-to-Treat (ITT) Population:  
The ITT population will be defined as all subjects who are randomized to double-blind study 
drug at Visit 7 and subsequently received at least one dose of study medication, and have one 
subsequent modified Ashworth and CGIC score at the same assement. 
 
Per Protocol (PP) Population: 
The per protocol (PP) population will be defined as all subjects who are randomized to 
double- blind study drug at Visit 7, subsequently receive at least one dose of study 
medication, have at least one subsequent modified Ashworth and CGIC score at the same 
assement, and do not have any important protocol deviations.  Protocol deviaitions will be 
reviewed and subjects with important/not important violations will be identified prior to 
unblinding the clinical database.   
In addition, concomitant medications will be reviewed for anti-spasticity medication use, its 
dose, and the timing relative to the in-clinic assessment.  Adverse events will be reviewed in 
a similar fashion for confounding medical conditions.  Finally, confounding due to changes in 
physiotherapy regimen will be assessed.  In-clinic Ashworth assessments that are judged to 
be potentially confounded will be flagged.  The analysis of the PP population will exclude 
such potentially confounded assessments.  
Analyses of the primary efficacy endpoint will be repeated using the PP population if it 
differs in size from the ITT population in total number by more than 10% overall. 
 


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5.2 P-Values 
Unless stated otherwise, all significance tests will be two-sided with statistical significance 
(alpha, α) assessed at the 5% level.  All p-values will be reported to four decimal places.  P-
values will not be adjusted to account for multiple comparisons. 
 
5.3 Procedures for Handling Missing Data and Outliers 
Every effort will be made to collect all the data and avoid missing data.  For intention–to-
treat (ITT) efficacy data, multiple sensitivity analyses will be completed.  Further details 
about sensitivity analyses can be found in Section 6.2.1.6.  
 
All missing values will be queried and resolved to the best possible extent.  Unless 
specifically noted otherwise, missing values will not be imputed. 
 
5.4 Interim Analysis 
An interim analysis will not be performed. 
 
5.5 Blinded Review of Data 
The checking and assessment of data to revisit the proposed methods of statistical analysis for 
the purpose of finalizing the planned analysis prior to the breaking of the blind will be 
conducted by 
The following lists some of the aspects of the blinded data 
review that would be considered: 
 
• Checking of data for important/not important protocol deviations; 
• Precise determination of analysis populations (intent-to-treat, per-protocol, and 
safety), especially which subjects will be included and which will be excluded from 
these populations;  
• Handling of missing data; 
• Outlier identification in the data and specific decisions taken on  how  these will  be 
handled; 
• Reviewing and identifying concomitantly used medications that have potential anti- 
spasticity or neurological effects; 
• Reviewing and identifying changes in physiotherapy regimens; 
• Reviewing and identifying adverse events for potential confounding of modified 
Ashworth scores. 
 
The blinded data review will be discussed with SPARC Ltd. and will be documented in 
agreed and signed meeting minutes. 


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5.6 Final Reporting and Analysis 
The randomization code will be broken at the end of the trial when all subjects have 
completed the study and only after all data have been entered into the database, cleaned, anti-
spasticity medication use identified, and the database locked.  Prior to the final unblinding, a 
review to identify the Per Protocol population will be undertaken.  After database lock, the 
results will be analyzed and unblinded to the CRO statistician, programmer, and Sponsor. 
All analyses outlined in the protocol and in this SAP will be carried out after: 
• The SAP has been approved; 
• The study database has been authorized by the study clinical team as complete 
and final; 
• All analysis populations are determined; 
• Treatment Failures have been identified; and 
• Protocol deviations have been identified. 
Further exploratory analyses not necessarily identified in this SAP may be performed to 
support the clinical development program.  Any post hoc or unplanned analyses performed 
and not identified in this SAP will be clearly identified in the CSR. 
 
5.7 Multi-center Studies 
There are expected to be approximately 75 study sites in this study.  Due to the large number 
of study sites and the small numbers of subjects per site, the analysis of efficacy endpoints 
will not include adjustments for study site. 
 


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6. STATISTICAL ANALYSIS METHODOLOGY  
All data collected for this study will be presented in summary tables, figures, and listings 
(TFLs) as indicated in Appendix 1 of this SAP.  Shells for TFLs with enough detail for 
programming will be provided as a guide to develop the programming SAS codes. These 
shells will be in sufficient detail to simulate the actual TFLs when they are created from the 
locked database.    
Appropriate descriptive statistics will be computed and displayed (by time point and other 
key variables as appropriate) for both continuous and categorical variables.  For continuous 
variables, descriptive statistics will include n (the number of subjects with non-missing data), 
mean, standard deviation (SD), median, 95% confidence interval, minimum and maximum 
values.  For categorical data, the number and percentage of subjects within each category will 
be presented.  The denominator for percentages will be based on the number of subjects with 
non-missing data appropriate for summary purposes.  Unless otherwise noted, all percentages 
will be presented to one decimal place. 
 
Individual data listings of all data represented on the eCRF and from the clinical laboratory 
will be presented. 
 
6.1 Study Subjects 
6.1.1 Subject Disposition  
The final study disposition of each subject will be captured in the eCRF.  For those subjects 
who do not complete the study as planned, all potential reasons for discontinuation should be 
provided, with one indicated as primary.  The reasons for discontinuation will be categorized 
as described below and the following descriptive summaries of study disposition will be 
provided. 
 
• Number of subjects who were enrolled in each phase of the study (Part 1, Part 2, 
Part 3): 
o Part 1: Received 
 at Visit 1 
o Part 2: Received 
 at Visit 2 (Safety Population) 
o Part 3:  
 Randomized at Visit 7 
 Dispensed Blinded Study Drug at Visit 7 (Safety Population Part 3) by 
treatment group and overall 
 Intent-to-Treat Population by treatment group and overall 
 Per Protocol Population by treatment group and overall 
• Number and proportion of subjects (overall for Parts 1 and 2 and by treatment group 
and overall for Part 3) who discontinued each phase of the study. 
• Number and proportion of subjects (overall for Parts 1 and 2 and by treatment group 
and overall for Part3) who dropped-out for each of the following categories (based 
on primary reason and also based on all reasons) for why a subject may be 
prematurely discontinued from the study. 


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o Withdrew Consent 
o Adverse Event 
o MS-related Disease Progression 
o 
 
 
o Required Dose Change Between Visit 4 and Visit 11 
o Major Protocol Deviation 
o Lost to Follow-up 
o Worsening of Clinical Condition or Loss of Efficacy 
o Withdrew, Per Sponsor 
o Withdrew, Per Investigator 
o Other 
 
A listing of subject disposition will be prepared, inclusive of dates of last dose and last 
contact, and any investigator comments regarding reason for discontinuation. A summary 
table will tabulate overall disposition of the subjects by the categories above. A CONSORT 
figure will summarize subject disposition. 
6.1.2 Demographics 
Descriptive summaries of the Safety Population will be prepared for the demographic and 
baseline (Screening) parameters listed below.  Categorical variables will be described with 
counts and percentages and continuous variables with mean and 95% confidence interval 
(CI). These variables will also be summarized for the ITT population (and also for the PP 
population if it differs from the ITT population by more than 10% in overall sample size). 
• Age (years) 
• Age Group (<65 vs. ≥65) 
• Gender 
• Race/ethnicity 
• 
 
• Height (cm) 
• Weight (kg) 
• BMI (kg/m2) 
• 
 
 
 
 
 
 
  
 
 
6.1.3 Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or 
procedure defined in the protocol.  


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A subset of the protocol deviations can be identified as an important protocol deviation as 
described below: 
Important Protocol Deviation: A protocol deviation that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly 
affect a subject’s rights, safety, or well-being. Important deviaitons include 
includion/exclusion criteria violations, cases where withdrawal criteria developed but 
the subject was not withdrawn, receiving the wrong treatment or incorrect dose, and 
receiving excluded concomitant medications. 
 
Upon soft lock of the database, all documented protocol deviations in the study will be 
reviewed to identify all important protocol deviations by a data review team including 
representatives from clinical operations, medical, data management, and statistics, and sent to 
the sponsor for approval. Final decisions will be documented and databased. 
Protocol violations during Part 3 will be summarized by treatment group for the ITT 
population, and all protocol violations and deviations will be listed. 
6.1.4 Medical and Surgical History 
Medical history at Visit 1 (prior conditions and present conditions) will be coded using 
version 15.0 of the Medical Dictionary for Regulatory Activities (MedDRA®) and tabulated 
by system organ class and preferred term.  A by subject listing will also be created.  
6.1.5 Multiple Sclerosis History 
Multiple sclerosis history at screening will be summarized by MS type, MS duration (years), 
course severity, symptoms/signs symmetrical, time since last relapse (months), for the ITT 
and Safety Populations. This information will also be presented in a data listing. 
6.1.6 Spasticity History 
Spasticity history at Screening will be summarized by duration of spasticity (years), daily 
frequency before treatment, 
 
 for the ITT and Safety Populations. This information will also be 
presented in a data listing.  
6.1.7 Concomitant Medications 
Prior and concomitant medications will be coded using the most current version available of 
the World Health Organization Drug Dictionary (WHODRUG) March 2012.  These will be 
summarized based on Anatomical Therapeutic Chemical (ATC) classification level 3 and 
Preferred Name, using incidence and percentage.   
Neurological and anti- spasticity concomitant medications, identified during blinded data 
review, will be summarized separately overall for Part 2 and by treatment group and overall 
for Part 3 using counts and percentages and will be listed for all subjects. 
Medications used only during Screening and/or the run-in 
 treatment (i.e., discontinued 
prior to the first dose of 
 will be considered Prior Medications.  
These will be summarized separately. 


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A Concomitant Medication is defined as a medication that was started prior to the first dose 
of 
 and that continued for at least 1 day following the start of 
 or that was started after the start of 
 
. 
Concomitant medications will be summarized separately for Parts 2 and 3.  Concomitant 
status will be re-confirmed for Part 3. 
When medication start and/or stop dates are missing, the following imputations will be made 
(subject to medical review): 
• Missing Medication Start Dates 
1. If onset date is completely missing, then onset date is set to date of first dose 
2. If year is present and (month and day are missing), or (month is missing but day is 
present):  
a. If year = year of first dose, then set date to first dose date 
b. If year < year of first dose and medication stop month and year are 
available, then set to first of the end month 
c. Otherwise if year < year of first dose, then set month and day to December 
31st.  
d. If year > year of first dose, then set month and day to January 1st.  
3. If month and year are present and day is missing:  
a. If year=year of first dose and  
i. If month = month of first dose then set day to day of first dose date  
ii. If month < month of first dose then set day to last day of month  
iii. If month > month of first dose then set day to first day of month  
b. If year < year of first dose then set day to last day of month  
c. If year > year of first dose then set day to first day of month  
 
4. If the medication start date is completely missing and the corresponding stop date 
is completely missing, the medication start date will remain missing. 
• Missing Medication Stop Dates 
If the stop date is completely missing, the stop day will not be estimated (i.e., the 
medication will be assumed to be continuing). 
If only the day of Medication stop is unknown, the day will be assumed to the last of 
the month (e.g. ??-JAN-2011 will be treated as 31-JAN-2011). 
A by-subject listing comprehensive of prior and concomitant medications will be generated, 
inclusive of verbatim and coded terms, doses and routes, and start and stop dates.  Prior 
medications will be flagged.  Prior and concomitant status with respect to study drug 
treatment will be determined based on imputed dates as defined above.  Prior medications 
used within 30 days of Screening will be provided in a separate listing. 


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6.2 Efficacy Analysis 
6.2.1 Primary Efficacy Analysis 
6.2.1.1 Modified Ashworth Score 
The first and best known scale for measuring the degree of spasticity was the Ashworth 
scale, first developed in 1964 for use in a multiple sclerosis therapeutic trial.  Spasticity 
accounts for much of the disability affecting lower limbs.  Modified Ashworth score for the 
12 movements of the lower extremities that will be measured will be evaluated as one of the 
primary efficacy parameters.  The Ashworth assessment is the current standard for clinical 
assessment of lower extremity spasticity and the most commonly used tool to evaluate the 
efficacy of pharmacologic and rehabilitation interventions for treatment of spasticity. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The 6-point modified Ashworth scale scores are presented below: 
 
Score     :   Analysis Value :   Degree of Muscle Tone 
0            :  
 
0  
:  No increase in tone 
1 
:    
1  
:  Slight increase in muscle tone, manifested by a catch, followed  
 
 
  
 
    by minimal resistance at the end of the range of movement  
 
 
  
 
   when the affected part(s) is moved in flexion or extension 
1+ 
:     
2  
:  Slight increase in muscle tone, manifested by a catch,  
 
 
  
 
    followed by minimal resistance throughout the remainder  
 
 
  
 
   (less than half) of the range of movement 
2 
:    
3  
:  More marked increase in muscle tone through most of the  
 
 
  
 
    range of movement, but affected part(s) easily moved 
3            :     
4  
:  Considerable increase in muscle tone, passive movement difficult 
4            :  
 
5  
:  Affected part(s) rigid in flexion or extension 
*note:  A change from 1 to 1+ and from 1+ to 2 will each be counted as a 1-point change 
 
For the purposes of summaries and analyses, the analysis value above will be presented. 
 
6.2.1.2 Clinical Global Impressions of Change (CGIC) 


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CGIC will be assessed at Visits 4, 7, 8, 9, 10, and 11.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The 7-point scale for CGIC is presented below: 
Scale     :   Overall impression 
0            :    Not assessed 
1            :    Very much improved 
2            :    Much improved 
3            :    Minimally improved 
4            :    No change 
5            :    Minimally worse 
6            :    Much worse 
7            :    Very much worse 
 
 
6.2.1.3 Derivation of Primary Endpoint 
The primary efficacy variable is the proportion of subjects who become a Treatment Failure 
during the double-blind randomized withdrawal part (Part 3). Using the primary efficacy 
variable, the CRO will perform a determination of failures (the blinded failure analysis). A 
subject’s response status will be determined after database lock, but prior to unblinding the 
data. A subject who meets the following criterion will be considered a treatment failure: 
• A CGIC of ≥ 5 (“minimally worse” to “very much worse”) and at least one 
movement with a ≥ 1 unit increase in MAS from Baseline (A change from 1 to 1+ 
and 1+ to 2 will be counted as a 1-unit change) 
 
The MAS at a given visit will be recorded for each of the 12 movements measured.  
 
 
 
 
For the Treatment Failure analysis, subjects who provide MAS and CGIC scores at Visit 11 
and meet the treatment failure criterion at Visit 11, 
 
 
 
 


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All other subjects will be classified as not being Treatment Failures. 
 
6.2.1.4 Null Hypothesis of the Primary Effiacy Analysis 
The null hypothesis is that there is no difference in the failure rates between
 
 groups. The alternative hypothesis is that there is a difference in 
the failure rates between the 
 groups. 
 
6.2.1.5 Primary Efficacy Analysis 
The primary efficacy analysis will be performed using the intent-to-treat (ITT) population. 
 
 
 
The primary efficacy analysis will be carried out using a two-sided test at the 
alpha=0.05 level of significance. 
 
 
.  Alternate approaches to handling missing data are discussed 
in Section 6.2.1.6. 
 
6.2.1.6 Sensitivity Analysis of the Primary Efficacy Analysis 
Several sensitivity analyses of the impact of missing data on the primary efficacy endpoint 
will be performed.  First, the primary efficacy analysis will be repeated in the PP 
population if it differs in size from the ITT population by more than 10% overall.  In 
addition, the primary efficacy analysis will also be performed (using the ITT population) 
with different assumptions regarding the response status of a subject with missing data.  
 
  
 
 
 
  
 
 
 
  
 
 
 
 
6.2.2 Secondary Efficacy Analyses 
6.2.2.1 Subject Global Impression of Severity (SGIS) 


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Subjects will be asked to rate their overall impression of severity at Visits 4, 7, 8, 9, 10, and 
11. At each of these visits, the subject is to be asked “Overall, how would you rate the 
severity of your spasticity over the past week?” 
 
The 7-point scale for SGIS is presented below: 
Scale     :   Overall impression 
0            :    Not assessed 
1            :    Normal, no spasticity 
2            :    Borderline spasticity 
3            :    Mild spasticity 
4            :    Moderate spasticity 
5            :    Marked spasticity 
6            :    Severe spasticity 
7            :    Worst spasticity imaginable 
 
6.2.2.2 Secondary Analysis of SGIS 
The difference between treatment groups in SGIS scores at Visit 11 will be analyzed 
 
 
 
 
 
 
 
If Visit 11 is missing, the last available SGIS will be used. 
 
6.2.3 Additional Efficacy Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The exploratory analyses described below will be performed on the ITT population.  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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6.2.4.5 
Time Since Last Dose 
Because the timing of post-dose of assessments is a factor potentially related to efficacy, time 
from prior dose to modified Ashworth assessment will be summarized descriptively for each 
visit in Part 3 (Visits 8, 9, 10, 11), by treatment group.  
 


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6.2.4.6 
Subgroup Analyses 
Exploratory analyses will be performed to investigate the effect of different subgroups 
on the primary outcome treatment failure analysis. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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6.3 Safety Analysis 
6.3.1 Adverse Events 
All adverse events will be coded using version 15.0 of MedDRA, which will be noted in the 
CSR. 
 
Adverse events reported as pre-existing at the start of the run-in 
 or that 
emerge during the 
 treatment phase will be considered pre-treatment adverse 
events; these will be flagged in a listing. 
 
A treatment-emergent adverse experience (TEAE) is defined as any event that only 
occurred after 
 administration or that existed before drug 
administration but increased in severity or treatment attribution.  
 
 
 
The duration of an AE will be calculated as: 
 
Duration = (AE End Date – AE Onset Date) + 1 
 
When AE start and/or stop dates are missing, the following imputations will be made 
(subject to medical review): 
•    Missing AE Start Dates 
 
1. If onset date is completely missing, then onset date is set to date of first dose 
2. If year is present and (month and day are missing), or (month is missing but day is 
present):  
a. If year = year of first dose, then set date to first dose date 
b. If year < year of first dose and medication stop month and year are 
available, then set to first of the end month 
c. Otherwise if year < year of first dose, then set month and day to December 
31st.  
d. If year > year of first dose, then set month and day to January 1st.  
3. If month and year are present and day is missing:  
a. If year=year of first dose and  


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i. If month = month of first dose then set day to day of first dose date  
ii. If month < month of first dose then set day to last day of month  
iii. If month > month of first dose then set day to first day of month  
b. If year < year of first dose then set day to last day of month  
c. If year > year of first dose then set day to first day of month  
 
4. If the AE start date is completely missing and the corresponding stop date is 
completely missing, the AE start date will remain missing. 
 
•    Missing AE Stop Dates 
 
If the stop date is completely missing and the event is not ongoing (i.e., an 
outcome is indicated), the stop day will not be estimated. 
 
If only the day of resolution is unknown, the day will be assumed to the last of the 
month (e.g. ??-JAN-2011 will be treated as 31-JAN-2011) 
 
If the stop date is completely missing and the event is ongoing, the event will be 
noted as “Ongoing” in the stop date column in the AE listings. 
 
The incidence of TEAEs and serious adverse events (SAEs) will be summarized 
 
 
 
 
An overall summary of TEAEs will include: 
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 
 
The incidence of TEAEs will be presented by system organ classification and preferred 
terms, by highest relationship, by treatment-related status (possibly, probably, 
certainly), by highest severity, by descending order of frequency of preferred terms, by 
dose at earliest onset for all possible dose groups, and by discontinuation status. 
 
In addition, separate summaries of TEAEs will be prepared with subjects categorized by 
sex, age (below 65 years of age and 65 years of age and older), race, and renal impairment 
category (see Section 6.1.2). 
 


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The effects of concomitant medications and/or medical conditions present at screening will 
also be explored.  Should any medications be used by or conditions be present in 20% or 
more of the subjects overall, subjects will be categorized accordingly and the incidence of 
TEAEs in each part summarized.  Additional drugs or diagnoses of interest may be 
identified during the blinded data review. 
 
The incidence of treatment-emergent serious adverse events (SAEs) will be presented by 
system organ classification and preferred terms, by treatment-related status (possibly, 
probably, certainly), and for those that are fatal. 
 
Adverse events will be listed for all subjects, including verbatim and coded terms. 
6.3.2 Clinical Laboratory Tests 
The following tests will be performed at Screening and Visit 7 (end of open-label fixed 
dose phase or upon early discontinuation): 
 
Hematology: 
• Red blood cell indices, including RBC count, hemoglobin, and hematocrit 
• Total WBC count 
• Differential WBC count 
• Platelet count 
Serum chemistry (Full Panel): 
• Sodium 
• Potassium 
• Chloride 
• 
CO2 
• Glucose (random) 
• BUN 
• Creatinine 
• Calcium 
• ALT 
• AST 
• Alkaline phosphatase 
• Total bilirubin 
• Total protein 
• Albumin 
Urinalysis: 
• Dipstick for pH, specific gravity 
• Microscopic examination of the sediment 
• Urine pregnancy test (for women) to be performed at Screening, Visit 4 (Week 6), 
and Visit 7 (Week 14) 
 


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Scheduled laboratory testing will be performed at a central laboratory using sex- and age- 
appropriate normal ranges.  Laboratory tests may also be repeated between scheduled 
visits at the discretion of the Investigator.  In addition, repeat testing should be performed 
at the end of the study to follow any clinically significant abnormality to 
resolution/stabilization. 
 
Clinical laboratory testing (hematology, chemistry, and urinalysis) results at each visit 
(Screening and Visit 7) and its change from Screening (for all continuous clinical laboratory 
parameters) will be summarized using descriptive statistics (n, mean, 95% confidence 
interval, standard deviation, minimum, median, and maximum) using Conventional units.  
Where applicable (e.g., red blood cell indices), results will be presented separately for men 
and women.  For the summary of change statistics, the Baseline mean and standard 
deviation will be provided for the subset of subjects with available data for the change 
summary.  Summaries will be based on values obtained from the central laboratory only and 
appropriate visit windows for categorizing results will be established prior to database lock 
and unblinding. 
 
When more than one laboratory value is available within a given visit window, the latest 
value will be used for tabulation purposes.   
 
Criteria for possibly significant changes have been established for selected parameters, 
tabulated below.  The numbers and percentage of subjects meeting these criteria will be 
summarized. 
 
PCS Hematology Values: 
 
 
 
 
 
 
 
 


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PCS Blood Chemistry Parameters 
 
 
Clinical laboratory results will be listed for all subjects, inclusive of flags for whether or not 
the value is outside laboratory normal range, considered significant by the Investigator, or 
meet the pre-specified criteria for being possibly clinically significant.  Normal ranges will be 
noted in the listing.  Values outside laboratory normal ranges as well as those considered 
clinically significant by the Investigator will be flagged as L (low) and H (high). 
 
6.3.3 Vital Signs 
Sitting diastolic and systolic blood pressures, resting pulse measurements, respiration, and 
body temperature (°C) at each visit will be summarized using descriptive statistics (n, mean, 
95% confidence interval, standard deviation, median, minimum, and maximum) for 
measurements during the open-label phase and also by treatment groups during the 
randomized double-blind withdrawal phase.  Similarly, change from Visit 1 at each visit 
will be summarized using descriptive statistics.  For the summary of change statistics, the 
Baseline mean and standard deviation will be provided for the subset of subjects with 
available data for the change summary.  Appropriate visit windows for categorizing 
results will be established prior to database lock and unblinding. 
 
For summary purposes, if more than one vital sign measurement is available for an analysis 
visit, then the latest value of each parameter will be used. 
Values considered possibly clinically significant by the Investigator are to be 
flagged.  Criteria for possibly significant changes are presented in the table below.  
Number and percentages of subjects with values of clinical significance will be 
summarized for each study Part; in Part 3, summaries will be by treatment group. 
 
 
 


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PCS Values for Vital Signs 
 
 
6.3.4 12-Lead ECG 
Electrocardiograms will be performed at Screening, Visits 2, 4, 7, and 11.  Only one 
assessment will be made at Screening, while assessments will be made in triplicate at later 
visits.  All triplicate results will be averaged for summary and analysis purposes.  
Parameters to be summarized include: HR, PR, RR, QRS, QT, and QTc.  The QTc interval 
will be presented by both the Bazett (QTcB = QT/(RR)½) and the Fridericia (QTcF = 
QT/(RR)⅓) corrections.  For QTcF and QTcB at each study visit, the distribution of 
maximum values (≤ 450, >450 - ≤ 480, >450 males, >470 females, >480 - ≤ 500, and > 
500 msec) as well as the distribution of the greatest change from Visit 2 (0 or less [no 
increase], 1-29 msec, 30-60 msec, > 60 msec, and >60 msec increase or >500 msec) will be 
presented. Appropriate visit windows for categorizing results will be established prior to 
database lock and unblinding. 
 
When more than one value is available within a given visit window, the latest value will 
be used for tabulation purposes. 
 
ECG results will be summarized by treatment group and visit.  Descriptive statistics will 
include mean, 95% confidence interval, standard deviation, median, minimum, and 
maximum.  Continuous ECG parameters will be summarized as change from Baseline (Visit 
2).  For the summary of change statistics, the Baseline mean and standard deviation 
will be provided for the subset of subjects with available data for the change 
summary.    Clinical interpretations will also be summarized by visit and treatment group.  
Any ECG abnormalities, based on clinical interpretation, will be listed. 
 
ECG results, including clinical interpretation and a flag for whether or not the value meets 
criteria for being possibly clinically significant, will be listed for all subjects. 
 
6.3.5 Physical Exam 
Complete physical examination is to be performed at Screening and, as needed in response 
to changes in medical history, at the final study visit (Visit 11, or earlier in the event of 
premature termination).  The complete examination will consist of evaluation of the skin, 
head, eyes, ears, nose, throat, neck, thyroid, lungs, heart, lymph nodes, abdomen, and 
extremities.  Brief, targeted physical examinations are to be performed at other visits as 
necessary in response to clinically significant adverse events. 


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Descriptive statistics will be provided for proportions of subjects with abnormalities on 
physical examination.  Physical examination findings will be listed.  These will be reviewed 
for any emergent abnormalities that could be attributed to the new dosage form. 
 
6.3.6 Neurological Examinations 
Neurological examination sufficient to establish the EDSS score is to be performed at 
Screening. The examination is to consist of an evaluation of mental status; corneal reflexes; 
extra-ocular movements; facial sensation (light touch); facial strength; palatal movement; 
tongue movements; neck extension; neck flexion; head turning; respiration; forced vital 
capacity; tendon reflexes of the  right  and  left  biceps,  triceps,  supinator,  quadriceps,  
and  ankle  (scored  as  0=absent, 1=reduced, 2 =normal,  3=increased,  4=clonus);  and  
plantar  stimulation  (scored  as  0=no movement or flexor; 1=extensor).  Targeted 
examination is to be repeated, as needed in response to  changes  in  medical history,  at  the  
final study  visit  (Visit  11,  or earlier  in  the event  of premature termination). 
 
Descriptive statistics will be provided for proportions of subjects with abnormalities on 
neurological examination.  Neurological examination findings will be listed. These will 
be reviewed for any emergent abnormalities that could be attributed to the new dosage 
form. 
 
6.3.7 Suicidality Assessments using C-SSRS 
The Columbia Suicide Severity Rating Scale (C-SSRS) is used to assess 
 
suicidal ideations and behaviors at Baseline, with monitoring prospectively thereafter at 
every subsequent visit. 
 
 
 
 
 
 
 
Frequencies of suicidal ideation and suicidal behavior at Baseline and during the trial (since 
last visit version) will be summarized.   
 
 
 
 
 
 
 
 


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7. TESTING/QUALITY CONTROL PLAN AND SOFTWARE/SYSTEM 
All statistical programs will be written in SAS® version 9.3, or later.  Statistical programs 
will be tested and reviewed for Quality Control (QC) by a second programmer/biostatistician 
not involved in the programming as per 
 standard operating procedure 
(SOP). In addition, 
 SOP will be followed to ensure that the information is complete, 
consistent, and accurately reflects the data stored in Clinical Data Management System 
(CDMS) database.  Further all tables, figures, and listings (TFLs) will undergo a QC process 
by an independent biostatistician/programmer to ensure that the information is complete, 
consistent, and accurately reflects the data stored in CDMS.  
 
7.1 Programming Specifications for TFLs 
Appendix 1 provides a list of all the TFLs that are planned to be produced. 
 
7.2 Formatting Conventions 
The following formatting conventions will be used to output TFLs:  
• TFLs are outputted by SAS Output Delivery System (ODS) into Rich Text 
Files (RTF) format. 
• Tables and Listings will include borders around all headings and data cells. 
• Output will be in landscape orientation with margins of 1.5 inches on top, and 
1 inch for right, left, and bottom. 
• The default font to be in tables/listings/figures will be Courier New.  
• Preferred and minimum font size: 
 
Portion of Output 
Preferred 
Minimum 
Page Header 
10 pt 
8 pt 
Title 
10 pt  
8 pt 
Column header 
10 pt  
8 pt 
Cells 
10 pt 
8 pt 
Footnote 
10 pt  
8 pt 
Page Footer 
10 pt 
8 pt 
 
• Data will be centered within columns when the maximum length of the data 
being displayed is less than or equal to the maximum width of the column 
heading. When the maximum length of the data being displayed exceeds the 
maximum width of the column heading, the data will be left-justified. 
• Column headings should be in initial capital characters.  For numeric 
variables, include “unit” in the column heading when appropriate. 
• In figures, axes will be labeled appropriately. 
  


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7.3 Standard Text Conventions 
7.3.1 Header 
All output (table, figure, or listing) will have the following header: 
 
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Protocol CLR_09_21       
 
 
 
Page xx of XX 
 
All output will have the date and time (date and time output was generated) and internal page 
number in the footer.  Tables/Figures/Listings should be internally paginated (i.e., page 
numbers should appear sequentially within each output). 
 
7.3.2 Title 
At least three (3) lines, in general, will be reserved for the entire title.  
• The first line is for the table/listing/figure number;  
• The second line is for the actual title; and  
• The third line is reserved for the analysis population descriptor.  
 Population(s) represented on the tables will be clearly identified in 
the last row of the table Title.  Consistent terminology will be used 
to identify a population.   
 Sub-population(s) or special population(s) descriptions will provide 
sufficient detail to ensure comprehension of the population (e.g., 
ITT Subjects from Study Site 1, Per-Protocol Subjects from Study 
Site 2) used for analysis in a table, figure, or a data listing. 
 
All titles will be centered, as shown in the following example: 
 
Table 14.3.2.1 
Overall Incidence of Safety Events 
Safety Population 
 
7.3.3 Footnotes 
Unless otherwise specified, footnotes will appear on all pages within the tables and listings as 
follows: 
• Footnotes will be in the format of  “Note: followed by 2 spaces, then 
the footnotes”, as shown in the following example:  
 
Note:  SD = Standard Deviation; SEM = Standard Error of the Mean. 
 
 
• Each line of a complete footnote should end with a period. 


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• When an abbreviation (e.g. AE, SAE, etc.) appears first time in the 
whole set of TFLs for a study, a footnote should be provided at least 
once; and it is up to the study statistician to decide whether there is a 
need to repeat the same footnote for the rest of TFLs.  
• A footnote serves as a brief explanation/clarification /definition 
/concept of a flag symbol or a character, an abbreviation, a 
terminology, etc., that appears in or relates directly to the displayed 
content of a table/listing/figure.  
• All footnotes will be at the lowest line of the page immediately above 
the footer.  There will be one space between the last footnote and the 
footer. 
• For Tables, first footnote will provide source listings and/or analysis 
datasets names for cross-referencing. 
 
7.3.4 Footer 
The following footer should appear at the very bottom of each page of a table, a listing, or a 
figure generated in SAS in the lower left corner: 
 
Program: PGNAME.sas; Creation Date and Time: DDMMMYYYY HH:MM 
Data Cutoff: DDMMMYY:HH:MM:SS – ADaM Generated MMM  DD, YYYY  
 
where PGNAME = SAS program name. 
 
 
7.4 Statistical Conventions 
7.4.1 Statistics Reported  
• Unless otherwise specified, the mean and median will be displayed to one more decimal 
place than the original value and the standard deviation to two more decimal places, 
while minimum and maximum will be reported in the format of the original data, e.g.:   
 
Original: xx 
Mean and median: xx.x 
SD: xx.xx 
Minimum and maximum: xx 
 
• Descriptive statistics in this template include: Mean, Median, Standard Deviation 
(SD), Q1, Q3, and N. In addition, 95% CI will be presented when appropriate.  
 
 
• Unless specified in the actual TFL shells for a study, all percentages will be rounded to 
2 decimal places in all tables/figures/listings, with the exception of adverse events, 
which will be rounded to 1 decimal place.  Rounding will take place after all 
calculations have been performed. 


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• Population summaries that include p-values will report the p-value to four decimal 
places with a leading zero (0.0001).  All p-values reported on default output from 
statistical software (i.e., SAS® Software) may be reported at the default level of 
precision.  P-values <0.0001 should be reported as <0.0001 not as 0.0000. 
 
• Use of N versus n: 
N = total number of subjects or subjects in the population. 
n = total number of subjects or subjects in the specific category. 
 
7.4.2 SAS Procedure Output 
If appropriate, SAS procedure output may be formatted and saved as source for references 
and will be included in Appendix.  
7.4.3 Tables Summarizing Categorical Data 
The following specifications apply to tables that summarize categorical data: 
• Percent of events should be left blank (including the parentheses) if the 
number of events is zero. 
• If the categories of a parameter are ordered, then all categories between 
the maximum possible category and the minimum category will be 
included, even if n=0 for a given category between the minimum and 
maximum level for that parameter. 
• If the categories are not ordered, then only those categories for which 
there is at least one subject represented will be included. 
• A missing category will be added to any parameter for which 
information is not available for any subjects. 
 
7.4.4 Subject Data Listings 
In general, individual subject data listings should include all subjects with data.  However, if 
a subject data listing includes only subjects who met a certain condition, and there were no 
subjects who met that condition, then a “message” will appear indicating that no subjects met 
the condition for inclusion in that listing. 
 
 
 


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8. REFERENCES 
 
 
 
 
 
ICH E3 (1995): Structure and Content of Clinical Study Reports. International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH). 
 
 
ICH E6 (1996): Guideline for Good Clinical Practice. International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH). 
 
ICH E9 (1998): Statistical Principles for Clinical Trials. International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH). 
 
MedDRA Version 15.0 (Mar 2012). International Federation of Pharmaceutical 
Manufacturers and Associations (IFPMA). 
 
SAS® for Windows® Version 9.3. SAS Inc. Cary, North Carolina USA. 
 
 
 
 
WHO Drug Dictionary (WHO-DD) (Mar 2012). World Health Organization (WHO) Uppsala 
Monitoring Center (UMC). 
 
 


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9.  APPENDICES 
9.1 Planned Tables, Listings, and Figures  
Tables and Figures: 
Table 14.1.1.1  
Screen Failure Summary (All Subjects) 
Table 14.1.1.2 
Subject Disposition (All Subjects) 
Table 14.1.2 
Protocol Deviations Part 3 (ITT Population) 
Table 14.1.3.1 
Demographics and Baseline Characteristics (ITT Population) 
Table 14.1.3.2 
Demographics and Baseline Characteristics in Part 2 (Safety Population) 
Table 14.1.3.3 
Demographics and Baseline Characteristics in Part 3 (Safety Population) 
Table 14.1.4  
Medical History (Safety Population) 
Table 14.1.5.1 
Multiple Sclerosis History (ITT Population) 
Table 14.1.5.2 
Multiple Sclerosis History (Safety Population) 
Table 14.1.6.1 
Spasticity History (ITT Population) 
Table 14.1.6.2 
Spasticity History (Safety Population) 
Table 14.1.7.1 
Prior Medications (Safety Population) 
Table 14.1.7.2.1 
Concomitant Medications  Part 2 (Safety Population) 
Table 14.1.7.2.2 
Concomitant Medications – Anti-Spasticity  Part 2(Safety Population) 
Table 14.1.7.2.3 
Concomitant Medications – Neurological Part 2 (Safety Population) 
Table 14.1.7.3.1 
Concomitant Medications  Part 3 (Safety Population) 
Table 14.1.7.3.2 
Concomitant Medications – Anti-Spasticity  Part 3 (Safety Population) 
Table 14.1.7.3.3 
Concomitant Medications – Neurological Part 3 (Safety Population) 
Table 14.1.8 
Physical Examination Results (Safety Population) 
Table 14.1.9 
Neurological Examination Results (Safety Population) 
Table 14.1.10.1.1 
Exposure Dose Levels Parts 1 and 2 (Safety Population) 
Table 14.1.10.1.2 
Acceptable Conversion Dose Levels at Week 6 Parts 1 and 2 (Safety Population) 
Table 14.1.10.1.3 
Dosing Compliance Parts 1 and 2 (Safety Population) 
Table 14.1.10.2.1 
Exposure Dose Levels Part 3 (Safety Population) 
Table 14.1.10.2.2 
Dosing Compliance Part 3 (Safety Population) 
 
 
Table 14.2.1 
Treatment Failure Rates (ITT Population) 
Table 14.2.2 
Subject Global Impression of Severity (ITT Population) 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.2.5  
Treatment Failure Rates by Gender (ITT Population) 
Table 14.2.6  
Treatment Failure Rates by Race (ITT Population) 
Table 14.2.7  
Treatment Failure Rates by Age Group (<65 or ≥65) (ITT Population) 


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Table 14.2.20 
Time To Dropout in Part 3 (ITT Population) 
 
 
Table 14.3.1.1.1 
Overview of Adverse Events in Part 2 (Safety Population) 
Table 14.3.1.1.2 
Incidence of Treatment-Emergent Adverse Events in Part 2 (Safety Population) 
Table 14.3.1.1.3 
Incidence of Treatment-Emergent Adverse Events by Descending Order of Frequency 
of Preferred Terms in Part 2 (Safety Population) 
Table 14.3.1.1.4 
Incidence of Treatment-Emergent Adverse Events by Maximum Severity in Part 2 
(Safety Population) 
Table 14.3.1.1.5 
Incidence of Treatment-Emergent Adverse Events by Highest Relationship in Part 2 
(Safety Population) 
Table 14.3.1.1.6 
Incidence of Treatment-Related Treatment-Emergent Adverse Events by Highest 
Relationship in Part 2 (Safety Population) 
Table 14.3.1.1.7 
Incidence of Treatment-Emergent Adverse Events Leading to Discontinuation in Part 
2 (Safety Population) 
Table 14.3.1.1.8 
Incidence of Treatment-Emergent Adverse Events by Gender in Part 2 (Safety 
Population) 
Table 14.3.1.1.9 
Incidence of Treatment-Emergent Adverse Events by Age Group in Part 2 (Safety 
Population) 
Table 14.3.1.1.10 
Incidence of Treatment-Emergent Adverse Events by Race in Part 2 (Safety 
Population) 
Table 14.3.1.1.11 
Incidence of Treatment-Emergent Adverse Events by Concomitant Medications in at 
Least 20% of Subjects in Part 2 (Safety Population) 
Table 14.3.1.1.12 
Incidence of Treatment-Emergent Adverse Events by Medical Conditions Present in 
at Least 20% of Subjects at Screening in Part 2 (Safety Population) 
Table 14.3.1.1.13 
Incidence of Treatment-Emergent Adverse Events by Renal Function in Part 2 (Safety 
Population) 
Table 14.3.1.1.14 
Incidence of Treatment-Emergent Adverse Events by Dose at Earliest Onset in Part 2 
(Safety Population) 
Table 14.3.1.2.1 
Overview of Adverse Events by Treatment Group in Part 3 (Safety Population) 
Table 14.3.1.2.2 
Incidence of Treatment-Emergent Adverse Events by Treatment Group in Part 3 
(Safety Population) 
Table 14.3.1.2.3 
Incidence of Treatment-Emergent Adverse Events by Descending Order of Frequency 
of Preferred Terms by Treatment Group in Part 3 (Safety Population) 
Table 14.3.1.2.4 
Incidence of Treatment-Emergent Adverse Events by Maximum Severity by 
Treatment Group in Part 3 (Safety Population) 


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Table 14.3.1.2.5 
Incidence of Treatment-Emergent Adverse Events by Highest Relationship by 
Treatment Group in Part 3 (Safety Population) 
Table 14.3.1.2.6 
Incidence of Treatment-Related Treatment-Emergent Adverse Events by Highest 
Relationship by Treatment Group in Part 3 (Safety Population) 
Table 14.3.1.2.7 
Incidence of Treatment-Emergent Adverse Events Leading to Discontinuation by 
Treatment Group in Part 3 (Safety Population) 
Table 14.3.1.2.8 
Incidence of Treatment-Emergent Adverse Events by Gender by Treatment Group in 
Part 3 (Safety Population) 
Table 14.3.1.2.9 
Incidence of Treatment-Emergent Adverse Events by Age Group by Treatment Group 
in Part 3 (Safety Population) 
Table 14.3.1.2.10 
Incidence of Treatment-Emergent Adverse Events by Race by Treatment Group in 
Part 3 (Safety Population) 
Table 14.3.1.2.11 
Incidence of Treatment-Emergent Adverse Events by Concomitant Medications in at 
Least 20% of Subjects by Treatment Group in Part 3 (Safety Population) 
Table 14.3.1.2.12 
Incidence of Treatment-Emergent Adverse Events by Medical Conditions Present in 
at Least 20% of Subjects at Screening by Treatment Group in Part 3 (Safety 
Population) 
Table 14.3.1.2.13 
Incidence of Treatment-Emergent Adverse Events by Renal function by Treatment 
Group in Part 3 (Safety Population) 
Table 14.3.1.2.14 
Incidence of Treatment-Emergent Adverse Events by Dose at Earliest Onset by 
Treatment Group in Part 3 (Safety Population) 
Table 14.3.2.1.1 
Incidence of Treatment-Emergent Serious Adverse Events in Part 2 (Safety 
Population) 
Table 14.3.2.1.2 
Incidence of Treatment-Related Treatment-Emergent Serious Adverse Events by 
Highest Relationship in Part 2 (Safety Population) 
Table 14.3.2.1.3 
Incidence of Fatal Treatment-Emergent Serious Adverse Events in Part 2 (Safety 
Population) 
Table 14.3.2.2.1  
Incidence of Treatment Emergent Serious Adverse Events by Treatment Group in 
Part 3 (Safety Population) 
Table 14.3.2.2.2 
Incidence of Treatment-Related Treatment-Emergent Serious Adverse Events by 
Highest Relationship in Part 3 (Safety Population) 
Table 14.3.2.2.3 
Incidence of Fatal Treatment-Emergent Serious Adverse Events in Part 3 (Safety 
Population) 
Table 14.3.4.1.1 
Vital Signs in Part 2 (Safety Population) 
Table 14.3.4.1.2 
Vital Signs in Part 3 (Safety Population) 
Table 14.3.4.1.3 
Potentially Clinically Significant Vital Signs in Part 2 (Safety Population) 
Table 14.3.4.1.4 
Potentially Clinically Significant Vital Signs in Part 3 (Safety Population) 
Table 14.3.4.2.1  
Hematology Laboratory Assessments (Safety Population) 
Table 14.3.4.2.2 
Hematology Laboratory Shift Table (Safety Population) 
Table 14.3.4.2.3 
Number and Percentage of Subjects with a Possibly Clinically Significant (PCS) 
Hematology Results – Safety Population 
Table 14.3.4.3.1  
Chemistry Laboratory Assessments (Safety Population) 
Table 14.3.4.3.2 
Chemistry Laboratory Shift Table (Safety Population) 
Table 14.3.4.3.3 
Number and Percentage of Subjects with a Possibly Clinically Significant (PCS) 
Chemistry Results – Safety Population 
Table 14.3.4.4 
Urinalysis Summary  (Safety Population) 
Table 14.3.4.5.1 
12-Lead Electrocardiogram Parameters in Part 2 (Safety Population) 
Table 14.3.4.5.2 
12-Lead Electrocardiogram Parameters in Part 3 (Safety Population) 
Table 14.3.4.5.3 
Clinical Interpretation and Categorical Results of 12-Lead Electrocardiogram in Part 
2 (Safety Population) 
Table 14.3.4.5.4 
Clinical Interpretation and Categorical Results of 12-Lead Electrocardiogram in Part 
3 (Safety Population) 


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Table 14.3.5.1  
C-SSRS Summary of Suicidal Ideation and Suicidal Behavior in Part 1 (Safety 
Population) 
Table 14.3.5.2  
C-SSRS Summary of Suicidal Ideation and Suicidal Behavior in Part 2 (Safety 
Population) 
Table 14.3.5.3  
C-SSRS Summary of Suicidal Ideation and Suicidal Behavior in Part 3 (Safety 
Population) 
 
 
 
Figures 
Figure 14.1.2.1 
Subject Disposition 
Figure 14.2.20.1 
Time to Dropout 
Figure 14.3.5.1.1 
Suicidal Ideation and Behavior Histogram – Part 1 
Figure 14.3.5.2.1 
Suicidal Ideation and Behavior Histogram – Part 2 
Figure 14.3.5.3.1 
Suicidal Ideation and Behavior Histogram – Part 3 
 
Listings 
Listing Number 
Title 
Population 
Listing 16.1.7 
Randomization Scheme 
All Enrolled 
Listing 16.2.1.1  
Subject Eligibility 
All Enrolled 
Listing 16.2.1.2  
Subject Disposition 
All Enrolled 
Listing 16.2.3.3 
Identification of Analysis Sets 
All Enrolled 
Listing 16.2.2 
Protocol Deviations  
All Enrolled 
Listing 16.2.4.1 
Demographics 
All Enrolled 
Listing 16.2.4.2.1 
Medical History 
All Enrolled 
Listing 16.2.4.2.2 
Surgical History  
All Enrolled 
Listing 16.2.4.2.3 
MS History 
All Enrolled 
Listing 16.2.4.2.4 
MS Symptoms Other Than Spasticity  
All Enrolled 
Listing 16.2.4.2.5 
Spasticity History 
All Enrolled 
Listing 16.2.4.3.1 
Prior and Concomitant Medications 
All Enrolled 
Listing 16.2.4.3.2  
Neurological and Anti-Spasticity Concomitant 
Medications 
All Enrolled 
Listing 16.2.4.3.3  
Medications Used within 30 Days Prior to 
Screening 
All Enrolled 
Listing 16.2.4.3.4 
Physiotherapy regimen 
All Enrolled 
 
 
 
Listing 16.2.5.1.1 
Dose Administration 
All Enrolled 
Listing 16.2.5.1.2 
Drug Distribution/Return 
All Enrolled 
 
 
 
Listing 16.2.6.1  
Treatment Failure Rates 
All Enrolled 
Listing 16.2.6.2.1  
Subject Global Impression of Severity 
All Enrolled 
Listing 16.2.6.2.2  
Clinical Global Impression of Severity 
All Enrolled 
Listing 16.2.6.3.1 
Subject Diary 
All Enrolled 
Listing 16.2.6.3.2 
Subject Diary Summary per Week 
All Enrolled 


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Listing 16.2.6.4 
EDSS 
All Enrolled 
Listing 16.2.6.5 
Modified Ashworth Scores 
All Enrolled 
Listing 16.2.7.1  
Adverse Events 
All Enrolled 
Listing 16.2.7.2  
Serious Adverse Events 
All Enrolled 
Listing 16.2.8.1  
Chemistry Laboratory Results 
All Enrolled 
Listing 16.2.8.2  
Hematology Laboratory Results 
All Enrolled 
Listing 16.2.8.3  
Urinalysis Laboratory Results 
All Enrolled 
Listing 16.2.9 
Vital Signs 
All Enrolled 
Listing 16.2.10  
12-Lead ECG 
All Enrolled 
Listing 16.2.11  
Physical Examination 
All Enrolled 
Listing 16.2.12  
Neurological Examination 
All Enrolled 
Listing 16.2.13.1  
C-SSRS: Suicidal Ideation (Safety Population) 
All Enrolled 
Listing 16.2.13.2  
C-SSRS: Intensity of Ideation  (Safety 
Population) 
All Enrolled 
Listing 16.2.13.3  
C-SSRS: Category of Attempt  (Safety 
Population) 
All Enrolled 
Listing 16.2.13.4  
C-SSRS: Actual Attempt Data (Safety 
Population) 
All Enrolled 
  
 
 
 
 
 
: