Efficacy and Safety of SPARC0921 in Subjects With Spasticity
Phase: PHASE3
Conditions: Spasticity
Sponsor: Sun Pharma Advanced Research Company Limited

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  Any unpublished information contained in it may not be disclosed to a third party without prior written approval 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.