Clinical trial NCT01797185
Conditions: Spasticity
Keywords: spasticity
Sponsor: Sun Pharma Advanced Research Company Limited
Start date: 2013-04-09; Completion date: 2017-10-01
Enrollment: 375 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Open-label, safety study of SPARC1104 in subjects with spasticity due to multiple sclerosis

Detailed description:
Safety study of SPARC1104

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: SPARC1104 modified dose regimen I intervention 2: SPARC1104 modified dose regimen II intervention 3: SPARC1104 modified dose regimen III
Intervention descriptions: intervention 1: Subjects who exited study CLR\_09\_21 intervention 2: Subjects who received prior treatment regimen I intervention 3: Subjects who received no prior treatment regimen

Protocol documents:
Prot_000.pdf: 
Study title: A Clinical Evaluation of the Safety of Baclofen ER Capsules (GRS) When Administered 
Once Daily to Subjects with Spasticity due to Multiple Sclerosis (MS): An Open Label, Long Term, 
Safety Trial 
Date of protocol: 17 Dec 2015 
NCT number: NCT01797185 


    
  
 
Protocol CLR_11_04 
Sun Pharma Advanced Research Company Ltd. 
Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
PROTOCOL 
A CLINICAL EVALUATION OF THE SAFETY OF 
 
 
 
 
WHEN ADMINISTERED 
 
 TO SUBJECTS 
 
 DUE TO 
MULTIPLE SCLEROSIS (MS):
 AN OPEN LABEL,
 LONG TERM,
 SAFETY TRIAL 
 
   
    
 
 
 
 
Protocol No. 
: 
CLR_11_04 
 
 
 
Version No./Date 
: 
01, 14 February 2012 
Amendment No./Date 
: 
02, 17 December 2015 
 
 
 
Investigational 
Product 
: 
    
 
 
 
 
 
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  Any unpublished information contained in it may not be disclosed to a third party without prior written 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 (IRB), 
an Independent Ethics Committee (IEC) or a statutory regulatory authority under a similar condition of 
confidentiality. 
 


    
  
 
Protocol CLR_11_04 
Sun Pharma Advanced Research Company Ltd. 
Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
 
Confidential 
 
Page 2 of 47 
 
1. 
SYNOPSIS 
Name of Sponsor: Sun Pharma Advanced Research Company Ltd. 
Name of Investigational Product: 
    
 
 
Name of active ingredient 
 
Title of trial: A Clinical Evaluation of the Safety of 
    
 
 When Administered 
 
 to Subjects with Spasticity due to Multiple Sclerosis (MS): An Open Label, Long Term, 
Safety Trial 
Trial centers: Approximately 35-40 centers  
Trial period:  
The trial will continue until up to approximately 250 subjects 
have completed at least 26 weeks of treatment, of which 200 
subjects have completed at least 1 year of treatment.  
Phase of Development: 3 
 
Objectives: 
To investigate the long term safety of 
    
 
 when administered 
 
 in 
subjects with MS aged 18 years and above. 
Methodology:  
This is a multicenter, open-label, safety trial in subjects with spasticity due to MS. Approximately 550 
potential subjects will be screened to yield up to approximately 350 subjects enrolled from 
approximately 35-40 centers, in order to obtain safety data from at least 250 subjects who have 
completed at least 26 weeks of treatment and at least 200 subjects will have completed at least 1 year of 
treatment.  
 
    
  
   
    
    
  
  
  
   
  
  
   
  
    
  
  
  
  
  
 
     
    
  
      
 
  
    
 
 
  
   
  
    
  
 
  
 
  
 
Subjects who enroll in this trial and participated in the double-blind phase of study CRL_09_21 will 
temporarily receive blinded study medication during the first 4 weeks which will be dispensed using an 
electronic drug-dispensing system (IVRS/IWRS).  
 
All subjects will undergo safety assessments at Screening (Visit 1), Baseline (Visit 2), Week 4 (Visit 
3), Week 12 (Visit 4), Week 26 (Visit 5) and all follow-up visits conducted every three months. 
Number of subjects planned:  
Approximately 550 potential subjects will be screened to yield 350 subjects enrolled in approximately 
35-40 centers, in order to obtain safety data from at least 250 subjects who have completed at least 26 
weeks of treatment and at least 100 subjects will have completed at least 1 year of treatment.  
Diagnosis and inclusion/exclusion criteria: 
The trial will enroll male and female subjects, at least 18 years of age, with spasticity due to MS, who 
meet all eligibility criteria.  


    
  
 
Protocol CLR_11_04 
Sun Pharma Advanced Research Company Ltd. 
Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
 
Confidential 
 
Page 3 of 47 
 
 
Inclusion criteria: 
1. Willingness to participate and give written informed consent 
2. Men and women ≥ 18 years of age 
3. Sexually active women who are of child bearing potential will practice an acceptable method 
of birth control for the duration of the trial as judged by the investigator. Examples of 
acceptable contraception are: condoms, foams, jellies, diaphragm, intrauterine device, oral or 
long-acting injected contraceptives, bilateral tubal ligation, bilateral oophorectomy, 
hysterectomy, or having a partner who is incapable of initiating conception. The practice of 
contraception must have started at least 3 months prior to trial entry.  
4. If female, negative pregnancy test result at Screening 
5. Diagnosed with MS and a known history of spasticity 
6. Completed the double-blind randomized withdrawal phase (Part 3) of trial CLR_09_21 with no 
major protocol violation 
 
Exclusion Criteria: 
Subjects will be excluded from the trial if any of the following exclusion criteria apply prior to 
enrollment: 
1. History of hypersensitivity to 
 
2. History of alcohol abuse or use of recreational drugs within 12 months prior to Visit 1 
3. History of chronic use of concomitant medications in neurologic or psychiatric illness which 
would affect the assessment of the safety of the trial medication 
4. If the investigator feels that participation in this study is not in the best interest of the subject 
Investigational product, dosage and mode of administration, and batch number:  
    
 
  
               
    
 
  
  
  
  
  
 
Subjects enrolled following the completion of protocol CLR_09_21 will receive 
  
  
    
 
 as follows: 
 Subjects who were randomized to 
    
 
 in the double-blind part of 
study CLR_09_21 (Part 3) will continue to receive the same dose of 
 as they received 
in study CLR_09_21. 
 Subjects who were randomized to 
 in the double-blind part of study CLR_09_21 (Part 
3), will receive 
    
  
    
  
    
 
     
  
   
   the dose of 
    
 
 that they received in 
open-label fixed  
 dose phase (Part 2) of study CLR_09_21. 
 
Subjects enrolled in this study who participated in the double-blind phase of study CLR_09_21 will 
temporarily receive blinded study medication in the first 4 weeks dispensed according to the 
IVRS/IWRS.  
Duration of treatment: Subjects will continue to receive treatment for the length of the trial.  
Criteria for evaluation: 
 
Efficacy: This is a safety trial. Efficacy will not be formally evaluated. 
 
Safety: The following safety parameters will be evaluated: 


    
  
 
Protocol CLR_11_04 
Sun Pharma Advanced Research Company Ltd. 
Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
 
Confidential 
 
Page 4 of 47 
 
 Treatment Emergent AEs and concomitant medication assessments 
 Vital signs (seated blood pressure and pulse) 
 Clinical laboratory tests 
 12 lead electrocardiogram (ECG) 
 Physical examination and neurological evaluation 
 Columbia-Suicide Severity Rating Scale (C-SSRS) 
Statistical methods: 
Descriptive statistics, including the numbers, means, standard deviations, medians, minimums, 
maximums and 95% confidence intervals for continuous variables and the numbers and percentages for 
categorical variables, will be provided. Listings of individual subject’s data will also be produced. 
 
 
  
    
  
 
  
   
  
     
   
p 
  
  
 
 
 
Subset analysis will be stratified by concomitant anti-spasticity and MS medication used  
 
  if the percentage of subjects in these stratification groups is ≥10% of the total number 
of subjects enrolled.  


    
  
 
Protocol CLR_11_04 
Sun Pharma Advanced Research Company Ltd. 
Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
 
Confidential 
 
Page 5 of 47 
 
Table 1:  
Visits and Procedures Schedule 
Activities 
Day -14 
Day 1 
Day 28 
Day 84 
Day 182 
 
Week -2 
Visit 1 
(Screen)
a 
Week 1 
Visit 2 
(Baseline) 
Week 4 
± 5 days 
Visit 3 
Week 12  
± 5 days 
Visit 4 
Week 26  
± 5 Days 
Visit 5 / Premature 
Termination Visitb 
Visits 
Every 3 
Months  
± 5 daysc 
Informed consent 
X 
- 
- 
- 
- 
 
Medical history and 
demographics 
X 
- 
- 
- 
- 
 
Physical examination  
X 
- 
- 
- 
X 
 
Neurologic examination 
X 
- 
- 
- 
X 
 
Urine pregnancy test 
X 
- 
X 
X 
X 
X 
Vital signs (sitting) 
X 
- 
X 
X 
X 
 
Clinical laboratory tests
d 
X 
- 
- 
- 
X 
 
12-lead ECG
e 
X 
- 
X 
X 
Xe 
 
C-SSRS 
X 
- 
X 
X 
X 
X 
Concomitant medication 
and physical therapy 
assessments 
X 
X 
X 
X 
X 
X 
AE evaluation 
X 
X 
X 
X 
X 
X 
Dispense study 
medication 
X 
X 
X 
X 
X 
X 
Collect study  medication 
- 
X 
X 
X 
X 
X 
Dispense / collect subject 
diaries 
X 
X 
X 
X 
X 
X 
Schedule next visit 
X 
X 
X 
X 
X 
X 
aScreening Visit assessments in CLR_11_04  which are identical to final visit assessments in CLR_09_21 do not 
need to be repeated. The Screening Visit may be completed simultaneously with the final visit for CLR_09_21, 
and on the following day, if needed, provided drug supply from CLR_09_21 does not run out. Subjects cannot 
enter CLR_11_04 if drug supply runs out prior to the completion of the screening process.
 
bFor subjects not completing the study, all activities scheduled at this visit are to be conducted during the Premature 
Termination visit with the exception of the ECG (see footnote “e” below) and the physical and neurologic 
examinations. These three assessments may be conducted during the Premature Termination visit as needed in 
order to follow the resolution of any adverse events.  
cThese visits will be scheduled 90 (± 5) days following the previous visit. 
dHematology: red blood cell (RBC) count, hemoglobin, total white blood cell (WBC) count, differential WBC count, 
platelet count; serum chemistry: sodium, potassium, chloride, blood urea nitrogen (BUN), creatinine. 
eCompleted in triplicate two minute intervals during Visit 5. 12-lead ECG should be performed at the Premature 
Termination visit, as needed, in order to follow adverse events to resolution 
 


    
  
 
Protocol CLR_11_04 
Sun Pharma Advanced Research Company Ltd. 
Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
 
Confidential 
 
Page 6 of 47 
 
2. 
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................2 
2. 
TABLE OF CONTENTS .............................................................................................6 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
.............................11 
4. 
GENERAL INFORMATION 
.....................................................................................12 
4.1. 
Protocol Details ..........................................................................................................12 
4.2. 
Sponsor and Contract Research Organization (CRO) Details 
....................................12 
4.3. 
Person(s) Authorized to Sign the Protocol for the Sponsor 
........................................13 
4.4. 
Sponsor’s Medical Expert for the Trial 
......................................................................13
 
4.5. 
Investigator’s Agreement 
............................................................................................14
 
5. 
INTRODUCTION 
......................................................................................................15 
5.1. 
Background 
.................................................................................................................15
 
5.2. 
    
  
 
.....................................................................................16
 
5.2.1. 
Nonclinical Studies 
.....................................................................................................16 
5.2.2. 
Clinical Studies 
...........................................................................................................17 
5.2.3. 
Known and Potential Risks and Benefits 
....................................................................18 
5.3. 
Trial Rationale 
............................................................................................................19 
6. 
TRIAL OBJECTIVE AND PURPOSE 
......................................................................19 
7. 
TRIAL DESIGN 
.........................................................................................................20
 
7.1. 
Type and Design of Trial 
............................................................................................20 
7.2. 
Trial Endpoints ...........................................................................................................20 
7.3. 
Subject Number 
..........................................................................................................20 
8. 
SUBJECT POPULATION 
.........................................................................................20 
8.1. 
Number of Subjects 
....................................................................................................20 
8.2. 
Inclusion Criteria 
........................................................................................................21 
8.3. 
Exclusion Criteria 
.......................................................................................................21 
8.4. 
Withdrawal Criteria 
....................................................................................................21
 
9. 
TREATMENT OF SUBJECTS 
..................................................................................22 
9.1. 
Trial Medications 
........................................................................................................22 
9.2. 
Treatment Doses 
.........................................................................................................22 
9.2.1. 
Trial CLR_09_21 
........................................................................................................22 


    
  
 
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Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
 
Confidential 
 
Page 7 of 47 
 
9.3. 
Concomitant Medications 
...........................................................................................23 
9.4. 
Study Drug Administration 
.........................................................................................23 
9.5. 
Treatment Compliance 
................................................................................................23 
9.6. 
Withdrawal From the Study 
........................................................................................24 
9.6.1. 
Premature Discontinuation of Subject in the Trial 
.....................................................24 
9.6.2. 
Discontinuation of the Trial 
........................................................................................24 
10. 
SEQUENCE OF PROCEDURES 
..............................................................................24
 
10.1. 
General Conduct of the Trial 
......................................................................................25
 
10.2. 
Screening (Visit 1, Day -14 to Day -1/Week -2) 
........................................................25 
10.3. 
Baseline (Visit 2, Day 1/Week 1) 
...............................................................................25 
10.4. 
Visits 3 (Day 28 ± 5 days/Week 4) and 4 (Day 84 ± 5 days/Week 12) 
......................26 
10.5. 
Visit 5 (Day 182 ± 5 days/Week 26), or Premature Termination 
...............................26 
10.6. 
Visits Every 3 Months after Visit 5 (90  ± 5 days following Visit 5 and all 
subsequent visits) 
........................................................................................................26 
10.7. 
Unscheduled Visits 
.....................................................................................................27
 
11. 
PROCOTOL PROCEDURES 
....................................................................................27 
11.1. 
Enrollment 
..................................................................................................................27 
11.2. 
Assessment of Efficacy 
...............................................................................................27 
11.3. 
Assessment of Safety 
..................................................................................................27 
11.3.1. 
Adverse Events 
...........................................................................................................27
 
11.3.2. 
Serious Adverse Events 
..............................................................................................28
 
11.3.3. 
Pregnancy ...................................................................................................................28 
11.4. 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
...................................................................................................................29 
11.4.1. 
Eliciting, Documentation and Reporting of Adverse Events, Intercurrent 
Illnesses, and Subject Diaries 
.....................................................................................29 
11.4.1.1. Rating of Adverse Events 
...........................................................................................29 
11.4.1.2. Documentation and Reporting of Immediately Reportable Adverse Events 
..............31 
11.4.1.3. Follow-Up of Subjects after Adverse Events (Serious and Non-Serious) 
..................32 
11.4.1.4. Post-trial Events 
..........................................................................................................32 
11.4.2. 
Vital Sign Measurement 
.............................................................................................33
 
11.4.3. 
Clinical Laboratory Testing 
........................................................................................33 
11.4.4. 
12-Lead ECG 
..............................................................................................................33 


    
  
 
Protocol CLR_11_04 
Sun Pharma Advanced Research Company Ltd. 
Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
 
Confidential 
 
Page 8 of 47 
 
11.4.5. 
Physical and Neurological Examinations; Physical Therapy Assessments 
................34 
11.4.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
...................................................34 
12. 
STATISTICAL PLAN 
................................................................................................34 
12.1. 
Sample Size ................................................................................................................34 
12.2. 
Definitions 
..................................................................................................................35 
12.2.1. 
Safety Population 
........................................................................................................35
 
12.2.2. 
Observational Period ..................................................................................................35 
12.3. 
Statistical Analysis 
......................................................................................................35 
12.3.1. 
Demographics and Background Characteristics 
.........................................................35 
12.3.2. 
Trial Disposition and Dosing 
......................................................................................35 
12.3.2.1. Subject Disposition Criteria 
........................................................................................35 
12.3.2.2. Dosing 
.........................................................................................................................36
 
12.3.3. 
Analysis of Safety Variables ......................................................................................36 
12.3.3.1. Adverse Events 
...........................................................................................................36
 
12.3.3.2. Vital Signs ..................................................................................................................37
 
12.3.3.3. Clinical Laboratory Tests ...........................................................................................37 
12.3.3.4. 12-Lead ECG 
..............................................................................................................37 
12.3.3.5. Physical and Neurological Examinations 
...................................................................37 
12.3.3.6. Suicidality Assessment using C-SSRS 
.......................................................................37 
12.3.4. 
Prior and Concomitant Medications 
...........................................................................38
 
12.3.5. 
Subset Analysis 
...........................................................................................................38
 
12.3.6. 
Interim analysis 
...........................................................................................................38 
12.4. 
Procedure for Amendments to Statistical Plan 
...........................................................38 
13. 
TRIAL DRUG MANAGEMENT 
..............................................................................38 
13.1. 
Packaging and Labeling 
..............................................................................................38 
13.2. 
Blinding 
......................................................................................................................39 
13.3. 
Storage 
........................................................................................................................40 
13.4. 
Administration 
............................................................................................................40
 
13.5. 
Accountability 
.............................................................................................................40 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
.........................................40 
14.1. 
Monitoring 
..................................................................................................................40 
14.2. 
Documentation at the Trial Site 
..................................................................................40 


    
  
 
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Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
 
Confidential 
 
Page 9 of 47 
 
14.3. 
Subject
's Data and Data Protection 
.............................................................................41 
14.4. 
Data Management and Analysis 
.................................................................................41
 
14.5. 
Amendments to the Protocol ......................................................................................42 
14.5.1. 
Emergencies 
................................................................................................................42 
14.5.2. 
Protocol Violations/ Deviations 
..................................................................................42 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................43 
16. 
ETHICS 
......................................................................................................................43 
16.1. 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
..............43 
16.2. 
Ethical Conduct of the Trial .......................................................................................44 
16.3. 
Subject Information and Consent 
...............................................................................44 
17. 
DATA HANDLING AND RECORD KEEPING 
......................................................44 
18. 
FINANCING AND INSURANCE 
.............................................................................45
 
19. 
PUBLICATION POLICY 
..........................................................................................45
 
20. 
REFERENCES 
...........................................................................................................46
 
21. 
APPENDIX 
.................................................................................................................47 
 


    
  
 
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Sun Pharma Advanced Research Company Ltd. 
Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
 
Confidential 
 
Page 10 of 47 
 
LIST OF TABLES 
Table 1: Visits and Procedures Schedule 
....................................................................................5 
Table 2:
 Criteria to Rate Treatment Relationship of Adverse Events ......................................30 
 


    
  
 
Protocol CLR_11_04 
Sun Pharma Advanced Research Company Ltd. 
Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
 
Confidential 
 
Page 11 of 47 
 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Definition 
AE 
Adverse event 
AUC 
Area under the concentration-time curve  
BUN 
Blood urea nitrogen 
Cmax 
Peak plasma concentration 
Cmin 
C-CASA  
Trough plasma concentration 
Columbia Classification Algorithm of Suicide Assessment 
CNS 
Central nervous system 
CRO 
C-SSRS 
Contract research organization 
Columbia-Suicide Severity Rating Scale 
ECG 
Electrocardiogram  
eCRF 
Electronic case report form 
 
 
GABA 
Gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
 
 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug application 
 
 
IRB 
Institutional Review Board 
MedDRA 
Medical dictionary for regulatory activities 
mg 
Milligram(s)  
mL 
Milliliter(s) 
mm 
Millimeter  
MS 
Multiple sclerosis 
ng 
Nanogram(s) 
PI 
Principal Investigator 
QC 
Quality control 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SOP 
Standard operating procedures 
SPARC 
Sun Pharma Advanced Research Company 
Tmax 
Time to peak concentration 
WBC 
White blood cell 
 


    
  
 
Protocol CLR_11_04 
Sun Pharma Advanced Research Company Ltd. 
Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
 
Confidential 
 
Page 12 of 47 
 
4. 
GENERAL INFORMATION 
4.1. 
Protocol Details 
Protocol Title: 
A Clinical Evaluation of Safety of 
    
 
 when Administered 
 
 in Subjects with 
Spasticity due to MS: An Open Label Safety Trial 
Protocol Number: 
CLR_11_04 
Version No./ Date: 
01/ 14 Feb 2012 
Amendment No./ Date: 02/ 17 Dec 2015 
4.2. 
Sponsor and Contract Research Organization (CRO) Details 
Sponsor: 
 
Name: 
Sun Pharma Advanced Research Company Ltd. 
Address: 
  
  
 
 
  
  
  
  
      
 
Phone: 
  
 
Fax: 
  
 
 
 
CRO: 
 
 
  
  
 
 
 
  
  
    
  
 
 
     
 
 
     
 


    
  
 
Protocol CLR_11_04 
Sun Pharma Advanced Research Company Ltd. 
Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
 
Confidential 
 
Page 13 of 47 
 
4.3. 
Person(s) Authorized to Sign the Protocol for the Sponsor 
 
  
 
 
 
 
 
   
  
   
 
 
 
 
  
    
  
  
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
Signature                       Date 
 
 
 
 
 
 
 
 
4.4. 
Sponsor’s Medical Expert for the Trial 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
_________________________________________ 
Signature                                       Date 


    
  
 
Protocol CLR_11_04 
Sun Pharma Advanced Research Company Ltd. 
Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
 
Confidential 
 
Page 14 of 47 
 
4.5. 
Investigator’s Agreement 
As the Investigator of this clinical trial, I confirm that I have read and understood the protocol. I 
agree to suitably brief my team and supervise the conduct of this clinical trial in conformity with 
the Good Clinical Practice guidelines of the International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use as well as the 
relevant laws, rules and regulations currently in force in my state and country. 
 
Investigator’s Printed Name : ___________________________________________ 
 
 
Title 
 
 
: ___________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
Date (dd mmm yyyy) 
 


    
  
 
Protocol CLR_11_04 
Sun Pharma Advanced Research Company Ltd. 
Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
 
Confidential 
 
Page 15 of 47 
 
5. 
INTRODUCTION 
This protocol describes a clinical study designed to investigate the long term safety of 
 
  
 
 when administered 
 
 in subjects with spasticity due to multiple 
sclerosis (MS). 
This clinical trial will be conducted in compliance with Good Clinical Practices (GCP) including 
the Declaration of Helsinki and all applicable regulatory requirements. 
5.1. 
Background 
MS is the most common neurological disease of young adults. MS is characterized by the 
appearance of scattered plaques of demyelinated axons in the central nervous system (CNS).  
The Multiple Sclerosis Association of America estimates that there are approximately 400,000 
individuals in the United States diagnosed with MS and about 10,000 new cases per year. As 
reviewed by Paisley et al, spasticity is a major contributor to disability in MS.
1 It is estimated that 
between 40 and 75% of all subjects are affected. The survey by the MS Society1 reported fatigue, 
spasticity (stiffness, spasms, or both), and problems with balance as the most commonly 
experienced symptoms. Overall, 64% of respondents reported muscle stiffness, 51% muscle 
spasms, and 74% reported stiffness, spasms, or both. Spasticity consists of an abnormal, 
velocity-dependent increase in the phasic and muscle tonic stretch reflexes, due to an abnormal 
integration of the nervous system motor responses to sensory input.   
   
   
    
 
  
  
   
   
  
     
  
  
      
   
    
  
  
     
   
  
    
  
  
    
 
 
    
  
      
 
 
  
  
     
    
  
  
 
 
 
     
  
    
   
     
  
  
  
   
  
   
  
     
  
  
  
 
    
  
  
   
  
  
 
 
    
  
  
  
 
  
     
 
   
 
  
    
  
  
      
  
  
  
 
   
  
 
  
  
   
 
     
   
  
  
  
  
  
 
      
  
 
  
 
 
    
 
  
  
  
 
   
  
   
   
   
    
  
   
 
 
 
  
 
 
   
        
  
     
 
  
  
  
  
  
  
  
   
     
 
  
   
  
  
      
  
 
  
 
  
  
    
    
  
  
  
  
  
    
 
    
  
  
   
.   


    
  
 
Protocol CLR_11_04 
Sun Pharma Advanced Research Company Ltd. 
Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
 
Confidential 
 
Page 16 of 47 
 
 
   
 
 
      
   
  
  
   
   
    
 
  
    
    
  
 
      
   
      
    
   
  
 
    
    
  
  
  
  
 
  
  
    
  
  
  
  
  
    
  
   
  
   
   
      
   
    
   
   
  
   
  
    
  
  
 
   
   
  
    
   
  
   
  
     
 
  
  
  
    
  
     
       
 
 
  
 
      
  
   
    
 
  
  
  
 
  
     
 
 
   
   
   
   
  
    
  
  
    
 
  
  
  
 
   
       
     
    
 
   
 
   
  
  
    
 
 
    
  
  
    
  
  
   
  
     
 
  
  
   
  
   
  
 
   
 
  
  
  
  
  
 
    
  
 
  
  
       
  
   
 
 
  
  
  
    
  
  
    
     
   
  
 
      
   
 
 
  
 
   
  
    
 
                  
    
  
  
  
  
 
     
  
  
  
  
      
  
   
   
  
  
      
 
  
  
   
   
  
       
  
  
     
    
      
   
    
  
 
    
 
  
      
  
  
  
   
   
    
  
  
     
 
    
  
  
  
     
    
  
  
  
   
  
  
   
  
   
 
  
  
  
  
    
  
     
  
 
  
   
    
    
     
   
       
  
  
  
      
    
 
  
   
      
 
5.2.1. 
Nonclinical Studies 
A comprehensive battery of nonclinical studies has been performed with 
. 
  
 
  
     
 
   
     
  
 
 
 
  
  
  
  
     
  
. Please refer to the 
Investigator’s Brochure
3 for a complete summary of nonclinical data for 
    
 
. 


    
  
 
Protocol CLR_11_04 
Sun Pharma Advanced Research Company Ltd. 
Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
 
Confidential 
 
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Sun Pharma Advanced Research Company Ltd. 
Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
 
Confidential 
 
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Protocol CLR_11_04 
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Ver 01, 14 Feb 2012; Amd 02, 17Dec 2015 
 
 
 
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. 
5.3. 
Trial Rationale 
Study CLR_11_04, Version 01 was an extension of trial CLR_09_21,6 which is being conducted 
to demonstrate the efficacy and safety of  
    
  
 for the treatment of 
spasticity due to MS  
 
  
  
   
   
  
  
  
  
  
   
 
  
  
  
  
 
    
  
   
  
  
     
  
  
    
   
    
    
  
    
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
    
  
  
  
  
  
 
 Safety data will be 
collected for at least 26 weeks to examine the continued long-term safety of  
   
  
 
All subjects will immediately or within 4 weeks of study entry, receive 
    
 
 at a dose titrated to achieve acceptable control of their spasticity symptoms,      
 
 
 
  
    
      
   
  
  
  
 
  
    
 
     
 
    
  
   
   
  
 
   
  
   
         
  
 
. 
6. 
TRIAL OBJECTIVE AND PURPOSE 
The objective of this study is to investigate the long term safety of 
    
 
 
when administered 
 
 to subjects aged 18 years and older. 


    
  
 
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7. 
TRIAL DESIGN 
7.1. 
Type and Design of Trial 
This is a multicenter, open-label, safety study in subjects with spasticity due to MS. 
Approximately 550 potential subjects will be screened to yield 350 subjects enrolled in 
approximately 35-40 centers, in order to obtain safety data from at least 250 subjects who have 
completed at least 26 weeks of treatment and at least 100 subjects will have completed at least 1 
year of treatment.  
Subjects enrolled in clinical trial CLR_09_21 who completed the double-blind randomized 
withdrawal phase (Part 3) of that trial will be eligible to participate in this trial.  
Informed consent will be obtained from subjects prior to the initiation of any trial-specific 
procedures.    
    
  
    
  
    
  
   
 
  
  
  
   
  
  
         .  
Visits are scheduled on: Days -14 (Week -2), 1 (Week 1), 28 (Week 4), 84 (Week 12), 182 
(Week 26), and during 3 month interval, follow-up visits. 
 
7.2. 
Trial Endpoints 
The trial endpoints to be evaluated are safety parameters including vital signs, clinical laboratory 
results, 12-lead electrocardiogram (ECG), physical examination and neurological examination 
results, and treatment emergent adverse events (AEs). 
 
7.3. 
Subject Number 
Subjects enrolling CLR_11_04 will retain the same subject number as was assigned to them in 
the CLR_09_21 trial. 
The subject number will uniquely identify each enrolled subject. The subject number will appear 
on all study documents relating to that subject and will be cross-referenced by the subject’s 
initials and age. 
8. 
SUBJECT POPULATION 
8.1. 
Number of Subjects 
Approximately 550 potential subjects will be screened to yield 350 subjects enrolled in 
approximately 35-40 centers, in order to obtain safety data from at least 250 subjects who have 
completed at least 26 weeks of treatment and at least 100 subjects will have completed at least 1 
year of treatment.  


    
  
 
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8.2. 
Inclusion Criteria 
Subjects are required to give written consent to participate in the trial. They will be informed that 
their primary medical practitioner and physiotherapist may be contacted to inform them of the 
trial and its conditions. Subjects must meet all entry criteria listed below. 
1. Willingness to participate and give written informed consent 
2. Men and women ≥ 18 years of age 
3. Sexually active women who are of child bearing potential will practice an acceptable 
method of birth control for the duration of the trial as judged by the investigator. 
Examples of acceptable contraception are: condoms, foams, jellies, diaphragm, 
intrauterine device, oral or long acting injected contraceptives, bilateral tubal ligation, 
bilateral oophorectomy, hysterectomy, or having a partner who is incapable of initiating 
conception. The practice of contraception must have started at least 3 months prior to trial 
entry. 
4. If female, negative pregnancy test result at Screening 
5. Diagnosed with MS and a known history of spasticity 
6. Completed the double-blind randomized withdrawal phase (Part 3) of trial CLR_09_21 
with no major protocol violation 
8.3. 
 Exclusion Criteria 
Subjects will be excluded from the trial if any of the following exclusion criteria apply prior to 
enrollment: 
 
  
  
 
2. History of alcohol abuse or use of recreational drugs within 12 months prior to Visit 1 
3. History of chronic use of concomitant medications in neurologic or psychiatric illness 
which would affect the assessment of the safety of the trial medication 
4. If the investigator feels that participation in this study is not in the best interest of the 
subject. 
 
8.4. 
Withdrawal Criteria 
The subject will receive oral and written information about the trial, 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 inform the investigator that 
he/she is leaving the trial. The subject will be encouraged to provide the reason for wishing to 
withdraw. The subject must return the trial drug as well as undergo early study termination 
procedures. 
The investigator must withdraw a subject from the trial in the following cases: 
 Occurrence of an AE which does not justify a continuation of the trial in that subject 


    
  
 
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 Major protocol violation which jeopardizes the interpretation of that subject’s data 
 
The following are additional justifiable reasons for removing a subject from the trial: 
 Subject experiences intolerable spasticity 
 Subject has a treatment related SAE 
 Subject becomes pregnant during the trial 
 If, in the investigator’s opinion, continuation in the trial would be detrimental to the 
subject’s well being 
9. 
TREATMENT OF SUBJECTS 
9.1. 
Trial Medications 
The study drug, 
    
 
 is manufactured by SPARC Ltd., India. 
 
  
  
   
                 
    
 
  
   
  
 
  
    
   
      
 
The batch numbers including the certificate of analysis and stability documentation will be 
maintained in the trial master file. 
9.2. 
Treatment Doses 
  
   
  
 
  
    
 
 
  
 
  
              
           
  
  
 
 
     
      
  
   
     
  
        
 
 
  
  
  
     
  
 Subjects are to maintain a Subject Diary 
(Appendix 1) to record missed doses and other events or issues. The clinic will review the diaries 
with the subjects during the subsequent visits.  
 
9.2.1. 
Trial CLR_09_21 
Study CLR_11_04 will open for enrollment while study CLR_09_21 is ongoing. Blinded study 
medication will be temporarily dispensed to all subjects enrolled into CLR1104 who have 
exited study CLR0921 for the first 4 weeks of the study. 
  
  
  
   
  
   
  
    
 
 
  
  
  
  
 
  
  
  
  
    
  
    
  
    
  
    
  
  
    
  
   
  
  
   
  
  
  
  
  
    
  
   
  
    
  
    
  
      
  
   
   
  
   
    
  
    
  
     
  
  
  
 
  
    
 
    
  
  
    
  
  
  
  Blinded study medication for subjects in the first month of study CLR_11_04 will 


    
  
 
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ensure that the blind in study CLR0921 is preserved. 
  
  
 
    
   
   
 
 
    
    
  
 
 
 
  
  
  
 
 
  
 
   
 
    
   
  
  
  
     
   
  
  
  
  
    
 
  
    
  
   
       
     
  
  
  
  
 
  
 
    
 
  
 
 
  
 
   
  
 
    
     
     
 
 
  
  
 
 
    
  
  
 
   
  
 
  
   
   
 
  
     
   
 
 
   
  
      
 
        
 
 
  
  
 
 
 
   
  
   
       
 
  
    
 
    
  
  
      
    
    
  
   
    
  
   
 
   
  
 
 
  
      
     
 
    
  
  
 
 
  
  
  
     
     
  
   
   
  
   
  
         
     
  
  
       
   
    
 
 
  
     
   
  
    
 
. 
 
9.3. 
Concomitant Medications 
All concomitant treatments must be appropriately recorded and described in the electronic case 
report form (eCRF). 
 
9.4. 
Study Drug Administration 
Subjects will be instructed to take study medication at the same time of day    
 
    
 
   
9.5. 
Treatment Compliance 
Treatment compliance will be measured on the basis of a capsule count by the investigator or 
his/her designee every time drug supplies are returned. Each subject will be instructed to bring 
the study medication (with the capsules that remain) with him/her to 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 study medication within the next 3 days. If the subject fails to do so, the capsule count will be 
recorded as “not available.”  
 
Subject Diary (Appendix 1): 


    
  
 
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A Subject Diary will be utilized to assess compliance and collect comments regarding any 
important problems or issues (missed dose, reason for missing dose, disturbing signs/symptoms, 
etc) associated with this trial. The clinic staff will review the diary during each visit. Comments 
that may suggest AEs will be reviewed with the subject to determine the actual presence of AEs. 
Any missed doses will be recorded in the diary, along with the reason for the missed dose. The 
diary will help confirm the level of drug compliance in this study.  
9.6. 
Withdrawal From the Study 
9.6.1. 
Premature Discontinuation of Subject in the Trial 
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 in the eCRF, and the primary reason for discontinuation 
will be selected: 1) adverse event; 2) major protocol violation; 3) lost to follow-up; 4) worsening 
of clinical condition or loss of efficacy; or 5) other (for which the reason should be clearly 
stated). 
As far as possible, all assessments and procedures scheduled for the end-of-trial visit must be 
performed on all subjects who receive trial medication but do not complete the trial according to 
protocol. The subject must return all unused investigational products.   
Subjects who are withdrawn from the trial due to AEs will be treated according to established 
acceptable medical practice and will be 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.   
9.6.2. 
Discontinuation of the Trial 
SPARC Ltd. may discontinue the trial at any time, for ethical, scientific, or business reasons.  
The investigator is entitled at any time to stop his or her participation in the trial 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 Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) and the regulatory authorities will be informed promptly and will 
be provided with the reasons for the termination or suspension by the investigator and SPARC 
Ltd., respectively. 
10. 
SEQUENCE OF PROCEDURES 
Table 1 summarizes all visits and study procedures by time point.  
Visits will be scheduled on: Days -14 (Week -2), 1 (Week 1), 28 (Week 4), 84 (Week 12), 182 
(Week 26), and at 3 month interval visits.  
 


    
  
 
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10.1. 
General Conduct of the Trial 
Written informed consent will be obtained for this trial by the Principal Investigator (PI) or 
his/her designee from all subjects before the performance of any protocol-specific procedure. 
10.2. 
Screening (Visit 1, Day -14 to Day -1/Week -2) 
All potential subjects who have not completed CLR_09_21 will complete all CLR_11_04 
assessments during the Screening Visit. 
  
 
  
  
    
   
  
 
  
     
   
    
  
     
 
 
    
  
   
       
  
   
  
  
  
 
 
  
  
  
  
 
 
 
  
  
 
  
 
  
  
    
     
     
 
 
 
 Written informed consent will be obtained 
 Medical history and demographic information will be obtained 
 A physical examination will be performed 
 A neurological examination will be performed 
 A urine pregnancy test will be performed (if applicable) 
 Vital Signs (sitting), after resting for 5 minutes, will be obtained 
 Clinical laboratory testing will be performed including hematology (red blood cell [RBC] 
count, hemoglobin, total and differential white blood cell [WBC] count, platelet count), 
and serum chemistry including sodium, potassium, chloride, blood urea nitrogen [BUN], 
and creatinine 
 A 12-lead ECG will be performed in triplicate  
  
 
     
  
  
    
     
 
  
    
  
     
    
  
  
    
    
  
  
   
    
   
 
  
   
 
 Concomitant medication and physical therapy will be recorded 
 Study medication and diary will be dispensed.   Study medication will be dispensed via 
IVRS/IWRS 
 The next trial visit will be scheduled 
10.3. 
Baseline (Visit 2, Day 1/Week 1) 
During this visit, the investigator will review all entry criteria, making certain that the potential 
subject meets all criteria. In addition, the following procedures will be performed:  
 AEs will be recorded for all subjects Concomitant medications will be recorded 
 Study medication and Subject diary collected and reviewed from previous visit for 
compliance 
 Study medication and diary will be dispensed via IVRS/IWRS 
 The next trial visit will be scheduled 


    
  
 
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10.4. 
Visits 3 (Day 28 ± 5 days/Week 4) and 4 (Day 84 ± 5 days/Week 12) 
 Vital Signs (sitting), after resting for 5 minutes, will be obtained 
 A 12-lead ECG will be performed in triplicate  
 
 
    
 
 Concomitant medication and physical therapy will be recorded 
 AEs will be recorded 
 A urine pregnancy test will be performed  
 Study medication and Subject diary collected and reviewed from previous visit for 
compliance 
 Study medication and subject diary will be dispensed 
 The next trial visit will be scheduled 
 
10.5. 
Visit 5 (Day 182 ± 5 days/Week 26), or Premature Termination 
 Physical and neurologic examinations will be performed during Visit 5, but will be 
performed as needed during the Premature Termination visit to follow the resolution of 
any adverse events 
 A urine pregnancy test will be performed  
 Vital Signs (sitting), after resting for 5 minutes, will be obtained  
 Clinical laboratory testing will be performed including hematology (RBC count, 
hemoglobin, total and differential WBC count, platelet count), and serum chemistry 
including sodium, potassium, chloride, BUN, and creatinine 
 A 12-lead ECG will be performed in triplicate. 12-lead ECG should be performed at the 
Premature Termination visit, as needed, in order to follow adverse events to resolution. 
 C-SSRS assessment will be performed 
 Concomitant medication and physical therapy will be recorded 
 AEs will be recorded 
 Study medication and Subject diary collected and reviewed from previous visit for 
compliance 
 Study medication and subject diary will be dispensed 
 The next trial visit will be scheduled 
 
10.6. 
Visits Every 3 Months after Visit 5 (90  ± 5 days following Visit 5 and 
all subsequent visits) 
 Concomitant medication and physical therapy will be recorded 
 AEs will be recorded 
 A urine pregnancy test will be performed  
 C-SSRS assessment will be performed 
 Study medication and Subject diary will be dispensed (for subjects continuing on 
treatment only) 


    
  
 
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 Study medication and Subject diary collected and reviewed from previous visit for 
compliance 
 The next trial visit will be scheduled  
 
 
10.7. Unscheduled Visits 
 Concomitant medication and physical therapy will be recorded 
 AEs will be recorded 
 Study drug dose may be adjusted per Sections 9.2.2 and 9.2.3 
 Study medication collected and reviewed for compliance 
 Study medication will be dispensed as required 
 The next trial visit will be scheduled 
 
11. 
PROCOTOL PROCEDURES 
11.1. 
Enrollment 
Enrolment should only occur once subject eligibility is confirmed. Each successive subject will 
be assigned a unique identification number.  
11.2. 
Assessment of Efficacy 
This is a safety trial and efficacy will not be assessed. 
11.3. 
Assessment of Safety 
The PI and/or the study staff will monitor the subjects throughout the trial period.  
The following safety assessments will be made: 
 AEs 
 Vital signs (seated blood pressure and pulse) 
 Clinical laboratory tests 
 12 lead ECG in triplicate 
 Physical examination and neurological evaluation 
 C-SSRS 
 
11.3.1. Adverse Events 
An AE is any untoward medical occurrence during treatment with a pharmaceutical product in a 
subject that does not necessarily have a causal relationship with the treatment being 
administered. An AE can therefore be any unfavorable and unintended sign (including an 


    
  
 
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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. 
An untoward medical event occurring prior to the start of study treatment does not meet the 
above mentioned definition of an AE. Nevertheless, pre-dosing medical history and physical 
examination anomalies must be documented in the appropriate section of the eCRF. Each subject 
will be queried for the occurrence of baseline medical anomalies or conditions prior to study 
drug administration. Included will be an assessment of their grade (mild, moderate, or severe). 
These events will be reported under medical history or physical examination. During and 
following a subject
's participation in this trial, the investigator must ensure that adequate medical 
care is provided to a subject for any AE, including clinically significant laboratory values, related 
to the trial. The subject will be treated and/or followed up until the symptom(s) returns to normal 
or stabilizes, as judged by the PI. For data management purposes, for subjects completing the 
study, follow-up information on AE will be terminated at 30 days from the time of onset of the 
adverse event. 
11.3.2. Serious Adverse Events 
An 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. 
11.3.3. Pregnancy 
A urine pregnancy test will be performed at Visit 1 and at all post-baseline visits. Subjects with a 
positive test will be excluded from further participation in the trial and the pregnancy will be 
monitored by the clinic to term. Sexually active women of child-bearing potential will be 
instructed to practice an acceptable method of birth control for the duration of the trial as stated 
in the entry criteria. However, if a subject becomes pregnant during the trial, the pregnancy will 


    
  
 
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be recorded as a significant medical event. The pregnancy will be followed until its outcome, and 
the outcome will be reported as a significant medical event. 
 
11.4. 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
11.4.1. Eliciting, Documentation and Reporting of Adverse Events, Intercurrent 
Illnesses, and Subject Diaries 
Information on AEs will be derived by questioning the subjects in general and unbiased terms 
(eg, "How do you feel?” or “How have you been feeling since the last study visit?”), by subjects
' 
spontaneous reports, or by observation. The subject diaries will also be reviewed with the subject 
for the presence of potential AEs. 
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, action taken, outcome, seriousness, and relationship to the trial medication. 
11.4.1.1. Rating of Adverse Events 
The following system will be used to assess treatment relationship as well as intensity of the 
AEs. 
 


    
  
 
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Table 2:  
Criteria to Rate Treatment Relationship of Adverse Events 
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 tofulfil 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. 
 
Certainly 
A clinical event, 
including laboratory 
test abnormality, 
 
1. It follows a plausible time sequence to drug intake, this means that there 


    
  
 
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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 a positive argument in sufficient detail to support the view that the drug 
is causally  involved, pharmacologically or pathologically; eg 
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 upon readministration of the drug (only if ethically correct 
ie, 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 intensity 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. 
 
11.4.1.2. Documentation and Reporting of Immediately Reportable Adverse Events 
The subject will be examined for any new medical conditions, worsening of the pre-existing 
ones, or change in the frequency of pre-existing medical condition. Any clinically significant 
change in pre-existing conditions, new conditions, or change in the frequency of pre-existing 
conditions post study drug dosing should be entered on the AE page of the eCRF and any 
medication given in response to the condition should be listed on the concomitant medication 
page. 
All SAEs, whether or not considered attributable to the study drug, must be reported, in the 
eCRF and 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 
 Investigational product(s) 
 Protocol number 
 Subject identification number, initials, sex and date of birth 


    
  
 
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 Description of the AE, reason for serious status, measures taken and outcome (if 
resolved) 
 Likelihood of drug causation of the adverse event assessed by the investigator. 
All SAE Reports must be reported to the Clinical Drug Safety Department of the CRO.  Copies 
will be then forwarded to the Sponsor and the Sponsor’s Designee for Regulatory Reporting 
within 24 hours of receipt.   
Reports will be addressed to: 
 
  
 
 
 
  
   
 
  
  
   
 
 
 
 
 
 
The investigator will report all SAEs to the IRB/IEC within 7 working days of the investigator 
becoming aware of the event. The investigator will inform the IRB/IEC about any SAE 
occurring during the course of this trial that could adversely affect the safety of the subjects or 
the performance of the trial. 
Any unexpected and study drug-related SAE, which is reported during the course of this study, 
will be expeditiously reported by the Sponsor or designee to the appropriate regulatory agencies 
as described in the relevant ICH (E6; Guideline for Good Clinical Practice) and FDA (Safety 
Reporting Requirements for INDs and BA/BE Studies) guidance documents. The reporting of 
any unexpected and drug-related SAE will be immediately shared with all participating 
investigators in the  
 program, as mandated in the referenced regulatory guidance 
documents. All SAEs must be reported, whether or not considered attributable to the study drug 
on a separate SAE Report Form. The information in the SAE Form will comprise of at least the 
data described above. 
11.4.1.3. Follow-Up of Subjects after Adverse Events (Serious and Non-Serious) 
11.4.1.3.1. Unresolved Events 
If an AE/SAE is present when the subject has completed the main trial period, the course of the 
event post-study must be followed as previously described. 
11.4.1.4. Post-trial Events 
Any AE/SAE that occurs within 30 days after the end of the trial should be reported. Such events 
will be included in the safety analysis of the trial.  


    
  
 
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AEs continuing after end-of-trial will be followed up by telephone or with visits at the discretion 
of the investigator. Any AE which remains unresolved after completion of the trial requires 
detailed evaluation and follow-up until the AE has been resolved or a reasonable explanation for 
its persistence is found. 
11.4.2. Vital Sign Measurement 
Vital signs will be measured at Visits 1, 3, 4, and 5. Measurements will be made with the subject 
in a seated position (after resting for at least 5 minutes). Vital sign results will be evaluated 
against pre-specified criteria for clinically significant changes.   
11.4.3. Clinical Laboratory Testing 
The following tests will be performed at Screening (Week -2), Visit 5 (Week 26), and the 
Premature Termination visit (if applicable): 
 Hematology: 
o RBC, including RBC count and hemoglobin 
o Total WBC count 
o Differential WBC count 
o Platelet count 
 Serum chemistry: 
o Sodium 
o Potassium 
o Chloride 
o BUN 
o Creatinine 
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 
Screening Visits and Visit 5 at the discretion of the investigator.   
11.4.4. 12-Lead ECG 
ECG will be performed at Visit 1 (Week -2), Visit 3 (Week 4), Visit 4 (Week 12), Visit 5 (Week 
26), and during the premature termination visit (if applicable).     
ECG measurements will be collected in triplicate 2 minutes apart and read at the site. The 
following intervals will be collected: PR interval, QRS, and ventricular rate; the presence of T-
waves will be noted.   
A clinically significant change in any post-dosing ECG will be reported as an AE. 
 


    
  
 
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11.4.5. Physical and Neurological Examinations; Physical Therapy Assessments 
Complete physical and neurological examinations are to be performed at Visit 1 (Week -2), Visit 
5 (Week 26), and the Premature Termination Visit (as needed during the Premature Termination 
visit to follow the resolution of any adverse events).   
The complete physical 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 AEs. 
The neurological 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).  
Concurrent physical therapy will be assessed at every visit.  
 
11.4.6. Columbia Suicide Severity Rating Scale (C-SSRS) 
  
  
  
  
  
 
   
   
  
  
 
  
 
   
  
  
 
  
  
  
 
  
    
   
  
  
   
  
  
  
 
 
     
   
      
 
 
 
   
 
 
 
     
     
   
  
  
  
  
   
   
 
  
  
 
  
 
 
    
  
  
   
  
   
   
    
    
      
    
 
   
    
      
     
        
 
  
  
  
    
 
      
  
  
 
 
  
   
 
 
 
12. 
STATISTICAL PLAN 
12.1. 
Sample Size 
Approximately 550 potential subjects will be screened to yield 350 subjects enrolled in 
approximately 35-40 centers, in order to obtain safety data from at least 250 subjects who have 
completed at least 26 weeks of treatment and at least 100 subjects will have completed at least 1 
year of treatment.  


    
  
 
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12.2. 
Definitions 
12.2.1. Safety Population 
The safety population will be all subjects who received at least one dose of 
   
 
 and have subsequent contact with the clinic.   
12.2.2. Observational Period 
At the time of the NDA submission, an interim report will be prepared and timed such that it will 
include at least 350 subjects enrolled in approximately 35-40 centers, in order to obtain safety 
data from up to approximately 250 subjects who have completed at least 26 weeks of treatment 
and at least 100 subjects will have completed at least 1 year of treatment.    
     
   
  
  
   
   
  
    
  
    
    
  
   
. 
 
12.3. 
Statistical Analysis 
12.3.1. Demographics and Background Characteristics 
Descriptive statistics of the safety population will be prepared for the demographic and baseline 
characteristics listed below, including the numbers, means, standard deviations, medians, 
minimums, maximums and 95% confidence intervals for continuous variables and the numbers 
and percentages for categorical variables, will be provided.  Listings of individual subject’s data 
will also be produced. 
 Age (years) 
 Sex 
 Race/ethnicity 
 Renal function (blood urea nitrogen and serum creatinine) 
 Duration of MS 
 Type of MS 
Medical history at Screening Visit (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.   
12.3.2. Trial Disposition and Dosing 
The following descriptive summaries of trial disposition and dosing will be provided.  
12.3.2.1. Subject Disposition Criteria 
 Number of subjects who were enrolled 
 Number and proportion of subjects who discontinued the trial prior to Visit 5 (Week 26) 


    
  
 
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 Number and proportion of subjects who discontinued for each of the following categories 
for why a subject may be prematurely discontinued from the trial (Section 9.6.1):   
o Discontinued Due to Adverse Event:  Subjects who are discontinued from the trial 
medication due to the occurrence of an AE will be recorded as dropouts.   
o Discontinued Due to Major Protocol Violation:  Subjects who are discontinued 
from the trial due to the occurrence of a major protocol violation will be recorded 
as dropouts.   
o Lost to Follow-Up:  Subjects available for evaluation in Visit 1, but not evaluated 
for subsequent visits will be considered as lost to follow-up.  
o Discontinued Due to Worsening of Condition: Subjects can be prematurely 
discontinued from the trial due to worsening of condition at the discretion of the 
investigator.   
o Discontinued Due to Other Reasons:  Subjects who are discontinued from the trial 
due to any other reason will be recorded as dropouts. The reason for 
discontinuation will be recorded.   
12.3.2.2. 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.   
For 
 
, the starting dose, titration frequency, and maintenance dose will be 
noted and presented using descriptive statistics 
 
12.3.3. Analysis of Safety Variables 
12.3.3.1. Adverse Events 
All AEs will be coded in a standardized manner for regulatory activities. All AEs will be coded 
by system organ classification and preferred terms according to the Medical Dictionary for 
Regulatory Activities (MedDRA®). A AE is defined as: any new event that occurred after 
    
  
 administration, a condition that existed before drug administration 
but increased in severity, or a condition that existed prior to drug treatment but increased in 
frequency of occurrence.   
Medical history and physical examination anomalies that existed prior to Visit 1 will be 
considered baseline, abnormal, medical conditions, and will be described in the medical history 
or physical examination CRFs. These will be summarized separately. 
The incidence of AEs and SAEs will be summarized by relationship to the trial treatment, 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. 
 


    
  
 
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The effects of concomitant medications and/or medical conditions present at Visit 1 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 AEs in each part 
summarized.   
12.3.3.2. Vital Signs 
Vital sign measurements Visits 1, 3, 4, and 5 will be summarized using descriptive statistics (n, 
mean, standard deviation, median, minimum, and maximum). 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 clinical significance will be summarized. 
In addition, vital signs data will be listed for all subjects, inclusive of flags for whether the value 
is clinically significant in the investigator’s judgment and whether it meets pre-specified criteria 
as being possibly clinically significant. 
12.3.3.3. Clinical Laboratory Tests 
Clinical laboratory testing (hematology and chemistry) results at Visit 1 relative to Visit 5 (Week 
26) will be summarized using descriptive statistics (n, mean, standard deviation, minimum, 
median, and maximum).  Change from Visit 1 to Visit 5 will also be summarized. 
Values outside the laboratory normal range as well as those considered clinically significant by 
the investigator are to be flagged as L (low) and H (high). Shift tables displaying the shift from 
laboratory normal range between Visit 1 and Visit 5 will be generated. Criteria for possibly 
significant changes will be established a priori for selected parameters. The numbers and 
percentages of subjects meeting these criteria will be summarized. 
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. 
12.3.3.4. 12-Lead ECG 
Any ECG abnormalities, based on clinical interpretation, will be listed and reviewed for any 
emergent abnormalities that could be attributed to the new dosage form. Proportion of subjects 
with change from baseline will be summarized. 
12.3.3.5. Physical and Neurological Examinations 
Descriptive statistics will be provided, by treatment group, for proportions of subjects with 
abnormalities on physical and neurological examinations. Physical and neurological examination 
findings will be listed. These will be reviewed for any emergent abnormalities that could be 
attributed to the new dosage form.  
12.3.3.6. Suicidality Assessment using C-SSRS 
 


    
  
 
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 No inferential testing is planned. Results of the C-SSRS and the C-
CASA categorization will be listed for each subject.  
12.3.4. 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 using 
counts and percentages and will be listed for all subjects. 
All recently used (within 30 days prior to Visit 1) concomitant medications will be listed for all 
subjects. 
Changes in physical therapy regimens (screening through final visit) will be assessed.  
12.3.5. Subset Analysis 
Subset analysis will be planned depending on concomitant 
   
 medication 
used,   
 
  
       
   
  
  
 
  
 of the total number of subjects enrolled. 
12.3.6. Interim analysis 
For regulatory purposes, interim reports of safety data accrued will be prepared annually 
following the statistical analysis described in the Section 13.3. 
 
12.4. 
Procedure for Amendments to Statistical Plan 
It is intended that all statistical analyses specified in this protocol will be performed. However, it 
is conceivable that due to the study observations, some scheduled analyses may not be 
performed. In addition, trial observations or analysis results may suggest the need for additional 
statistical analyses of the collected trial data. In either case, deviations (subtractions or additions) 
from the planned statistical analysis will be fully described in the final clinical trial report. 
13. 
TRIAL DRUG MANAGEMENT 
13.1. 
Packaging and Labeling 
Packaging and central distribution will be performed by 
 
  
  
  
    
  
  
       
     
  
   


    
  
 
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All used and unused supplies will be retrieved from the investigators at the end of the trial.  
All study medication labeling will contain all information required for compliance with 
regulatory requirements. The storage conditions for the trial medication will be described on the 
medication label. 
 
13.2. 
Blinding 
 
 
  
  
     
   
  
    
  
 
  
  
 
 
     
 
   
 
     
 
    
  
    
  
    
   
    
  
   
  
  
  
  
 
    
  
    
  
   
  
    
  
      
  
   
     
   
   
  
    
  
    
  
  
  
  
 
    
 
  
   
   
  
      
  
  
  
  
 
    
  
  
  
    
   
  
  
 
   
   
    
   
  
      
 
   
 
  
 
    
  
   
    
  
  
  
 
    
  
  
  
 
    
  
  
     
     
    
  
   
    
  
   
  
 
  
  
  
 
  
     
     
 
 
  
  
   
  
 
  
  
     
     
 
   
    
  
   
  
        
     
  
  
       
   
    
 
  
  
     
   
  
    
 
 
 


    
  
 
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13.3. 
Storage 
All trial mediation will be stored in a securely locked cabinet, 
      and protected 
from light and moisture. Access should be strictly limited to the investigators and their 
designees. Neither the investigators nor any designees may provide 
    
 
 to any subject not participating in this protocol. 
13.4. 
Administration 
See Section 9.2 of the protocol for details. 
13.5. 
Accountability 
  
    
    
       
  
   
 
  
   
     
     
   
  
 
  
  
 
  
     
 
  
  
    
  
  
   
 
When the trial 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 trial, 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 trial drug. 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Monitoring 
On-site monitoring will be performed before, during, and after the trial. The monitor will ensure 
that the trial is conducted, recorded and reported in accordance with the protocol, standard 
operating procedures (SOPs), GCP, and the applicable regulatory requirements. The monitor will 
check the accuracy and completeness of the eCRF entries, source documents, and other trial-
related records against each other. The investigator will provide direct access to source 
data/documents for trial-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 trial. The monitor will record the date of each visit together with a 
summary of the status and progress of the trial. Proposed actions will be confirmed with the 
investigator in writing. 
14.2. 
Documentation at the Trial Site 
All data relating to the trial 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.   


    
  
 
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At the beginning of the trial, a site master file will be established at the investigational site. The 
investigator will maintain the trial 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. 
Prior to the start of the trial, 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 trial-related monitoring, audits, and regulatory inspection, providing 
direct access to source data/documents. 
14.3. 
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 trial subject and used in lieu of the subject
's name when the investigator 
reports AEs and/or other trial-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 trial. 
The investigator must maintain a list of names and identifying information (eg, initials, date of 
birth, subject identification code) of all subjects enrolled in the trial. The investigator will keep 
the subject identification code list in the site master file. 
14.4. 
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 trial book. When the data for a subject are declared clean (all 
data entered, verified, validated and resolved) the case book will be frozen. At the close of the 
trial, after all data has been transmitted to the statistician for final analysis; the Sponsor will 
authorize final database lock. 


    
  
 
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The QC of data will be performed to ensure that data entry and verification have been performed 
correctly in accordance to predefined instructions.  
When the data have been entered, verified, and validated, the database will be locked for the 
analysis to start (Clean File). 
14.5. 
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 trial 
subject or when the changes involve only logistical or administrative aspects of the trial (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 investigators. Amendments 
will be signed off in the same way as the protocol.  
14.5.1. 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 trial. 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. 
14.5.2. 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 trial. 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 trial. Protocol waivers will be 
allowed on a case-by-case basis by the Sponsor’s project manager and the waiver will be 
documented.  
A protocol deviation may be defined as an occurrence when there is non-adherence to trial 
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 


    
  
 
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data quality or trial 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 trial; this decision will be made by the investigator in conjunction with 
the Sponsor.  
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 trial report.  
15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The investigator and the trial monitor (or designee) will to ensure that the trial staff receives 
appropriate training and that any information relevant to the conduct of this trial is forwarded to 
other staff as appropriate.  
Quality assurance and quality control systems are implemented and maintained using written 
SOPs to ensure that the trial 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 trial 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 trial.  
Regulatory authorities worldwide may also audit the investigator during or after the trial. The 
investigator should contact the Sponsor immediately if this occurs, and must fully cooperate with 
regulatory authority audits conducted at a reasonable time in a reasonable manner. 
16. 
ETHICS 
Before initiation of the study, Sponsor will seek permission from the regulatory authorities for 
conducting the trial. All documents required by the appropriate authorities will be submitted.  
Any notification/submission will be dated and contain sufficient information to identify the 
protocol. 
16.1. 
Independent Ethics Committee (IEC) or Institutional Review Board 
(IRB) 
This study will be initiated after the protocol is reviewed and approved by the appropriate 
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. 


    
  
 
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16.2. 
Ethical Conduct of the Trial 
This study will be carried out in conformity with GCP described in Guideline E6 of the ICH. 
This trial will also be carried out in conformity with the laws, rules, and regulations prevailing in 
the state and country of the investigational site. 
16.3. 
Subject Information and Consent 
Subjects 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 trial’s implications before deciding to participate. The subject will 
be provided with a 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 trial, eg, 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 trial.  
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 trial related 
procedure is performed. 
17. 
DATA HANDLING AND RECORD KEEPING 
The investigator must maintain all documentation related to this trial. Essential documents (as 
defined in the ICH Guideline for 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 trial 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 trial.  If the investigator retires, 
relocates or for other reasons withdraws from the responsibility of keeping the trial records, 
custody must be transferred and Sponsor notified in writing. 
Sponsor will notify the investigator in writing when the trial-related records are no longer 
needed. 


    
  
 
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18. 
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. 
19. 
PUBLICATION POLICY 
The CRO and investigators agree to keep strictly confidential all unpublished information and 
results concerning this trial. 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. 


    
  
 
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20. 
REFERENCES 
 
  
   
   
     
 
     
   
  
  
   
  
  
  
  
  
 
 
  
  
  
  
 
 
 
  
      
  
 
 
       
    
  
  
  
    
     
 
   
  
  
   
 
  
  
   
    
 
  
  
 
 
 
    
    
    
  
  
  
  
  
  
    
  
   
  
  
 
  
 
  
  
  
   
  
  
  
    
 
 
  
 
  
  
     
 
  
   
    
  
   
  
  
     
 
 



SAP_001.pdf: 
Study title: A Clinical Evaluation of the Safety of Baclofen ER Capsules (GRS) When Administered 
Once Daily to Subjects with Spasticity due to Multiple Sclerosis (MS): An Open Label, Long Term, 
Safety Trial 
Date of SAP: 30 Oct 2017 
NCT number: NCT01797185 


Statistical Analysis Plan 
Study Title: 
A Clinical Evaluation of the Safety of 
 
When Administered Once Daily to Subjects with Spasticity Due to 
Multiple Sclerosis (MS): An Open Label, Long Term, Safety Trial 
Protocol Number: 
Amendment  
CLR_11_04 
Version 01 Amendment 02 17 Dec 2015 
Sponsor: 
Sun Pharma Advanced Research Company Ltd., 
 
 
 
 
Sponsor Contact: 
 
Director, Biostatistics 
 
CRO: 
 
 
 
Version No./Date 
Version 1.0 / 30Oct2017 
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. 


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Signatory Page 
 
This Statistical Analysis Plan was reviewed and approved by: 
 
Author 
 
 
 
Senior Biostatistician 
 
Date  
Reviewer  
 
 
 
Senior Biostatistician, Director of Programming 
 
 
Date  
 
 
Approval 
 
 
  
Director, Biostatistics 
 
Date 
 
 
 
 
10/30/17
10/30/17
10/30/17


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REVISION HISTORY 
 
Version No. 
Version Date 
Description of Modifications 
0.1 
06Mar2017 
Original Document  
0.2 
18Apr2017 
Author Updates 
0.3 
29Oct2017 
Sponsor Updates 
1.0 
30Oct2017 
Final Document 


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TABLE OF CONTENTS  
 
Signatory Page ............................................................................................................................ 2 
1. 
List of abbreviations and acronyms ................................................................................ 6 
2. 
Introduction ....................................................................................................................... 7 
3. 
Study Overview ................................................................................................................. 8 
3.1 
Study Objectives .................................................................................................... 8 
3.1.1 
Study Objective ...................................................................................... 8 
3.2 
Study Design .......................................................................................................... 8 
3.2.1 
Sample Size Considerations .................................................................. 9 
3.2.2 
Randomization ....................................................................................... 9 
3.2.3 
Study Assessments Schedules .............................................................. 10 
4. 
Study Endpoints and Definitions ................................................................................... 11 
4.1 
Study Safety Endpoints ....................................................................................... 11 
4.2 
Study Definitions ................................................................................................. 11 
4.2.1 
Study Day ............................................................................................ 11 
4.2.2 
Baseline and Change from Baseline ................................................... 12 
5. 
Statistical Analysis General Considerations ................................................................. 12 
5.1 
Analysis Populations ........................................................................................... 12 
5.1.1 
Safety Population ................................................................................ 12 
5.1.2 
Safety Groups ...................................................................................... 12 
5.1.2.1 
Safety Group 1: Subjects who 
 12 
5.1.2.2 
Safety Group 2: Subjects who are on 
 
..................................................................... 13 
5.1.2.3 
Safety Group 3: Subjects Entering the Trial with no Prior 
Treatment with 
 ..................................................................... 14 
5.2 
P-Values................................................................................................................ 14 
5.3 
Procedures for Handling Missing Data and Outliers ...................................... 14 
5.4 
Interim Analysis .................................................................................................. 14 
5.5 
Final Reporting and Analysis ............................................................................. 15 
5.6 
Multi-center Studies ............................................................................................ 15 
6. 
Statistical Analysis Methodology ................................................................................... 16 
6.1 
Study Subjects ..................................................................................................... 16 
6.1.1 
Subject Disposition .............................................................................. 16 
6.1.2 
Demographics ..................................................................................... 17 
6.1.3 
Protocol Deviations............................................................................. 17 
6.1.4 
Medical and Surgical History ............................................................. 18 
6.1.5 
Prior and Concomitant Medications ................................................... 18 


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6.1.6 
Exposure and Compliance .................................................................. 19 
6.1.6.1 
Exposure .......................................................................... 19 
6.1.6.2 
Compliance ...................................................................... 20 
6.2 
Efficacy Analysis ................................................................................................. 21 
6.3 
Safety Analysis ..................................................................................................... 21 
6.3.1 
Adverse Events .................................................................................... 21 
6.3.2 
Vital Signs ........................................................................................... 24 
6.3.3 
Clinical Laboratory Tests ................................................................... 25 
6.3.4 
12-Lead ECG....................................................................................... 27 
6.3.5 
Physical and Neurological Examinations ........................................... 27 
6.3.6 
Suicidality Assessment Using C-SSRS................................................. 27 
6.4 
Subgroup Analysis .............................................................................................. 28 
7. 
Testing/Quality Control Plan and Software/System .................................................... 29 
7.1 
Programming Specifications for TLFs .............................................................. 29 
7.2 
Formatting Conventions ..................................................................................... 29 
7.3 
Standard Text Conventions ................................................................................ 30 
7.3.1 
Header ................................................................................................. 30 
7.3.2 
Title...................................................................................................... 30 
7.3.3 
Footnotes ............................................................................................. 30 
7.3.4 
Footer .................................................................................................. 31 
7.4 
Statistical Conventions ........................................................................................ 31 
7.4.1 
Statistics Reported ............................................................................... 31 
7.4.2 
SAS Procedure Output ........................................................................ 32 
7.4.3 
Tables Summarizing Categorical Data ............................................... 32 
7.4.4 
Subject Data Listings .......................................................................... 32 
8. 
References ........................................................................................................................ 33 
9. 
Appendices ....................................................................................................................... 34 
9.1 
Planned Tables, Listings, and Figures ............................................................... 34 
 
 
 


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1. LIST OF ABBREVIATIONS AND ACRONYMS 
Abbreviations and 
Acronyms 
Description 
AE 
Adverse event 
BUN 
Blood urea nitrogen 
C-CASA  
Columbia Classification Algorithm of Suicide Assessment 
CI 
Confidence interval 
CNS 
Central nervous system 
CRO 
Contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
 
 
ECG 
Electrocardiogram  
eCRF 
Electronic case report form 
ER 
Extended release 
GABA 
Gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
 
 
ICH 
International Conference on Harmonisation  
 
 
MedDRA 
Medical dictionary for regulatory activities 
mg 
Milligram(s)  
mL 
Milliliter(s) 
mm 
Millimeter  
MS 
Multiple sclerosis 
ng 
Nanogram(s) 
PCS 
Potentially Clinically Significant 
QC 
Quality control 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SDTM 
Study Data Tabulation Model 
SOP 
Standard operating procedures 
SPARC 
Sun Pharma Advanced Research Company 
TEAE 
Treatment emergent adverse event 
TLFs 
Tables, Listings and Figures 
WBC 
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_11_04, “A Clinical Evaluation of the 
Safety of 
 When Administered Once Daily to Subjects with 
Spasticity due to Multiple Sclerosis (MS): An Open Label, Long Term, Safety Trial.” 
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 1.0 Amendent 02,  17 Dec 2015 
• Electronic Case Report Form (eCRF), 24 Jun 2013 
 
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 
 Biostatistician is responsible for updating the SAP throughout 
the life of the study as needed.  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 
This is a clinical study designed to investigate the long term safety of 
 
 when administered once daily in subjects with spasticity due to multiple sclerosis (MS).  
 
This study is an extension of trial CLR_09_21, which was conducted to demonstrate the 
efficacy and safety of 
 
 This safety trial will enroll subjects from trial 
CLR_09_21 as well as subjects who did not participate in that trial 
 
 whose spasticity symptoms are stable, as well as 
subjects with spasticity who have no previous exposure to 
 treatment. Safety data 
will be collected for at least 26 weeks to examine the long-term safety of 
 
 
 
3.1.1 Study Objective 
The objective of this study is to investigate the long term safety of 
 
 when administered once daily to subjects aged 18 years and older. 
 
3.2 Study Design 
This is a multicenter, open-label, safety study in subjects with spasticity due to MS. 
Approximately 550 subjects will be enrolled in approximately 35-40 centers, in order to 
obtain safety data from at least 250 subjects who have completed at least 26 weeks of 
treatment and at least 200 subjects who have completed at least 1 year of treatment. 
 
 
Subjects enrolled in clinical trial CLR_09_21 who complete 
 
 that trial will be eligible to participate in this trial. In addition, 
subjects not enrolled in trial CLR_09_21 who are on a stable daily dose 
 
 
as well as 
naïve subjects will be eligible to participate in this trial.   
Informed consent will be obtained from subjects prior to the initiation of any trial-specific 
procedures. 
 
 
 
  
A Subject Diary (Appendix 1) will be utilized to assess compliance and collect comments 
regarding any important problems or issues (missed dose, reason for missing dose, disturbing 
signs/symptoms, etc) associated with this trial. The clinic staff will review the diary during 
each visit. Comments that may suggest adverse events (AEs) will be reviewed with the 
subject to determine the presence of AEs. Any missed doses will be recorded in the diary, 
along with the reason for the missed dose. The diary will help confirm the level of drug 
compliance in this study. 


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Visits are scheduled on: Days -14 (Week -2), 1 (Week 1), 28 (Week 4), 84 (Week 12), 182 
(Week 26), and during 3 month interval, follow-up visits. 
Table 1 in Section 3.2.3 presents the visit and procedures schedule. 
 
3.2.1 Sample Size Considerations  
Approximately 550 subjects will be enrolled, in order to obtain safety data from approximately 
250 subjects who have completed at least 26 weeks of treatment and at least 200 subjects who 
have completed at least 1 year of treatment. 
 
 
 
3.2.2 Randomization  
No randomization will occur in the study. 
 


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3.2.3 Study Assessments Schedules   
Study assessments are described in detail in the protocol, and summarized below in Table 1. 
Table 1: Visits and Procedures Schedule 
 


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4. STUDY ENDPOINTS AND DEFINITIONS 
4.1 Study Safety Endpoints 
The study endpoints to be evaluated are safety parameters including: 
• Vital signs 
• Clinical laboratory results 
• 12-lead electrocardiogram (ECG) results 
• Physical examination results 
• Neurological examination results 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Treatment Emergent Adverse Events (TEAEs).  
 
4.2 Study Definitions  
4.2.1 Study Day  
For purposes of describing days on study drug in data listings, data will be assigned a study 
day, relative to the start of study drug at either Visit 1 or Visit 2, depending on whether they 
are 
 roll-over subjects or non roll-over subjects. The following 
rules will be used (this numbering of days differs from the Study Days as described in the 
protocol): 
 
 Roll-over Subjects 
For events that occurred after the Visit 1: 
 
Study Day = visit date – date of Visit 1 + 1 
 For events occurred before study drug administration: 
 
Study Day = visit date – date of Visit 1 
 
Non 
 Roll-over Subjects 
For events that occurred after the Visit 2: 
 
Study Day = visit date – date of Visit 2 + 1 
 For events occurred before study drug administration: 
 
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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4.2.2 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 
Percent change from baseline (PCFB) will be calculated as follow: 
• PCFB (%) = 100*(Value at Visit - Baseline)/Baseline  
 
5. STATISTICAL ANALYSIS GENERAL CONSIDERATIONS  
5.1 Analysis Populations  
5.1.1 Safety Population 
The safety population will be all subjects who received at least one dose of Baclofen ER Capsules 
(GRS) during the study and have a subsequent contact with the clinic. Within the Safety 
Population, the following Safety Groups will be used for all summary and analysis purposes, in 
addition to an overall summary, derived from the three distinct sources (see Section 5.1.2): 
• Safety Group 1: Subjects who completed 
 Study 
CLR_09_21 
• Safety Group 2: Subjects who are on 
 at 
entry 
• Safety Group 3: Subjects Entering the Trial with no Prior Treatment
 
 
5.1.2 Safety Groups 
5.1.2.1 Safety Group 1: Subjects who exited the Study CLR_09_21 
Study CLR_11_04 will open for enrollment while study CLR_09_21 is ongoing. Blinded 
study medication will be temporarily dispensed to all subjects enrolled into CLR_11_04 who 
have exited study CLR_09_21 
 
 
 
 
 
 
 
 
 
 
 


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All potential subjects will review the informed consent document prior to receiving blinded 
study medication kits dispensed via IVRS/IWRS. Kits dispensed will be similar in 
appearance and packaging as dispensed during Part 3 of study CLR_09_21. 
 
 
 
 
 
The actual identity of the contents 
can be obtained only by breaking the blinding code.   
During Visit 3, and for the remainder of this study, open label kits will be dispensed to all 
subjects who completed CLR_09_21. 
 
 
 
5.1.2.2 Safety Group 2: 
 
Subjects entering the trial 
 will 
complete a Screening period (Visit 1) of up to 14 days to allow all potential subjects to 
review the informed consent form and complete the procedures 
 
 At Baseline (Visit 2), these subjects will start with 
 
 
 


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5.1.2.3 Safety Group 3: 
 
Subjects 
 will complete a Screening period (Visit 1) of up to 
14 days to allow all potential subjects to review the informed consent form and complete the 
procedures
 
 
 
Subjects receiving other anti-spasticity medications 
 
will have the starting dose determined according to the investigator’s 
medical judgment. 
 
 
 
5.2 P-Values 
Data presentations in this safety study will be descriptive. Unless stated otherwise, any 
significance tests will be two-sided with statistical significance assessed at the alpha (α) 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.  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 
For regulatory purposes, interim reports of safety data accrued will be prepared annually.    
Post-trial AEs not included in the trial safey database will be included in a separate 
pharmacovigilance database, which will be used for generating periodic safety reports. No 
formal interim analyses are planned for the study. 
 


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5.5 Final Reporting and Analysis 
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; 
• Protocol deviations have been identified. 
Any post hoc or unplanned analyses performed and not identified in this SAP will be clearly 
identified in the CSR. 
 
5.6 Multi-center Studies 
There are expected to be approximately 35-40 study sites in this study.  Due to the large 
number of study sites and the small numbers of subjects per site, the analysis of 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, listings, and figures 
(TLFs) as indicated in Appendix 1 of this SAP.  Shells for TLFs 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 TLFs 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), 95% confidence intervals, median, 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.   
 
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 following descriptive summaries of subject disposition will be provided:  
• Number of subjects who were enrolled 
• Number and proportion of subjects who discontinued the trial prior to Visit 5 (Week 
26) 
• Number and proportion of subjects who discontinued for each of the following 
categories for why a subject may be prematurely discontinued from the trial:   
o Discontinued Due to Adverse Event:  Subjects who are discontinued from the 
trial medication due to the occurrence of an AE will be recorded as dropouts.   
o Discontinued Due to Major Protocol Violation:  Subjects who are 
discontinued from the trial due to the occurrence of a major protocol violation 
will be recorded as dropouts.   
o Lost to Follow-Up:  Subjects available for evaluation in Visit 1, but not 
evaluated for subsequent visits will be considered as lost to follow-up.  
o Discontinued Due to Worsening of Condition: Subjects can be prematurely 
discontinued from the trial due to worsening of condition at the discretion of 
the investigator.   
o Discontinued Due to Other Reasons:  Subjects who are discontinued from the 
trial due to any other reason will be recorded as dropouts. The reason for 
discontinuation will be recorded.   
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 


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table will tabulate overall disposition of the subjects. A figure will diagram the overall 
disposition of the subjects. 
 
A summary of screen failure subjects will be tabulated by reason for screen failure. 
 
6.1.2 Demographics 
Descriptive statistics of the safety population will be prepared for the demographic and 
baseline characteristics listed below, including the numbers, means, standard deviations, 
medians, minimums, maximums and 95% confidence intervals for continuous variables and 
the numbers and percentages for categorical variables: 
• Age (years) 
• Age Group (<65 vs. ≥65) 
• Sex 
• Race/ethnicity 
• Renal function  
 
 
 
 
 
 
 
 
 
 
 
 
• Duration of MS (years) 
• Type of MS 
• Pregnancy prevention status for femal subjects 
• Height (cm) 
• Weight (kg) 
• BMI (kg/m2) 
Listings of individual subject’s data will also be produced. A summary table of demographics 
will be produced with descriptive statistics. 
 
6.1.3 Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or 
procedure defined in the protocol.  
A subset of the protocol deviations can be identified as a major protocol deviation as 
described below: 


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Major Protocol Deviation: A major 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 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 deviations will be listed by subject with major deviaitons flagged. 
 
6.1.4 Medical and Surgical History 
Medical history at Screening Visit (prior conditions and present conditions) will be tabulated 
using version 15.0 of the Medical Dictionary for Regulatory Activities (MedDRA®) by 
System Organ Class and Preferred Term, both with a summary of incidence by diagnosis and 
the proportion with any abnormality.  A by-subject listing will be created. 
 
6.1.5 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODD) March 2012.  These will be summarized overall and by Safety Group 
based on Anatomical Therapeutic Chemical Class 3 level (ATC 3), using incidence and 
percentage.   
Neurological and anti-spasticity concomitant medications, identified before data lock, will be 
summarized separately overall, and for each Safety Group using incidence and percentage, 
and will be listed for all subjects. 
Medications previously used (within 30 days of Visit 1) and before the on-study treatment 
will be considered Prior Medications.  These will be summarized separately. 
Physical therapy regimen will be summarized by visit using counts and percentages. 
Numbers of subjects with changes at post-baseline visits will also be summarized. 
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 


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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 be the last 
day 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. 
6.1.6 Exposure and Compliance  
6.1.6.1 Exposure 
Exposure data at each visit starting with Screening will be summarized overall and for each 
of the safety groups. Specifically, the numbers of subjects for each dose level will be 
summarized with counts and percentages, and descriptive summaries (mean, median, mode, 
and standard deviation) of dose at each visit will be provided.   
For each subject, total exposure duration will be calculated as the number of days the subject 
 
 
 
 
The exposure duration will be calculated as the date of last dose reported on the final status 
eCRF– date of first dose + 1.  In cases where the date of last dose is not reported or missing, 
the date of last dose will be considered the date of the last visit with drug return reported.  If 
no visit with drug return reported exists, exposure duration will be set to 1 day. 


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This exposure data will be summarized overall for the safety population, and by each of the 
three safety groups described in Section 5.1.2. 
 
 
 
 
 
 
Individual subject listings will be prepared. 
 
6.1.6.2 Compliance  
Compliance by Dispense/Return 
Treatment compliance will be measured on the basis of a capsule count by the investigator or 
designee every time drug supplies are returned. Each subject will be instructed to bring the 
study medication (with the capsules that remain) with him/her to 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 study medication within the next 3 days. If the subject fails to do so, the capsule 
count will be recorded as “not available.”  
The clinic will fill out the ‘Dispense/Return Study Medication’ Form, included in the eCRF 
book. This form will list each bottle dispensed, along with the bottle number, the date the 
bottle was dispensed, and the dose strength. This form will also list each bottle that was 
returned, along with the bottle number, the date the bottle was returned, along with the 
number of capsules returned.  
Based on this form, percent compliance will be calculated using the number of capsules 
dispensed minus the number of capsules returned, divided by the number of capsules 
intended to be taken.   
Average compliance will be summarized descriptively by visit, and for the study overall.   
The compliance for each visit is derived by the following. As an example, consider bottles 
dispensed at Visit X: 
1) The expected number of capsules will be determined as the difference between the 
last return date for all bottles dispensed at the given visit and the Visit X date. The 
expected capsules calculation takes into account if >1 capsule is taken daily. 
2) The capsules that were assigned at the scheduled visit X and not any unscheduled 
visit between visit X and the next scheduled visit are used in the calculation for Visit 
X 
 
 
 
 
 
3) If any bottle from Visit X is not returned/data is not available, the number of capsules 
returned is not countable and per the protocol will be classified as “not available”. 
The compliance for this visit will be missing in this case. 


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4) The compliance for Visit X will be calculated as the [number of capsules dispensed - 
returned]/[number expected] 
 
 
 
 
 
 
 
A further categorical summary of compliance will be provided by visit, and for the study 
overall, using the following categories: <75%, ≥75% to ≤125%, and >125%. 
 
Secondary Compliance by Diary 
A Subject Diary will be utilized to assess compliance and collect comments regarding any 
important problems or issues (missed dose, reason for missing dose, disturbing signs/symptoms, 
etc) associated with this trial. The clinic staff will review the diary during each visit. Comments 
that may suggest AEs will be reviewed with the subject to determine the presence of AEs. Any 
missed doses will be recorded in the diary, along with the reason for the missed dose. The diary 
will help confirm the level of drug compliance in this study.  
For each subject, based on the subject’s diary data, percent compliance will be calculated 
based on recorded dose information divided by intended dosage.  The format of the summary 
of diary-based compliance information will follow that of the eCRF-based mothod above. 
This measure of compliance is only meant to endorse the preceding more rigorous measure 
based on the drug accountability data, which will be collected in the eCRF.    
A summary table of compliance by both Dispense/Return eCRF and Diary will be presented 
by Safety Group and overall. 
6.2 Efficacy Analysis 
This is a safety trial. Efficacy will not be formally evaluated.  
 
6.3 Safety Analysis 
6.3.1 Adverse Events 
Adverse events recorded from the time the Informed Consent Form is signed until 30 days 
after the end of the trial will be captured in the trial safety database. For any AE included in 
this trial’s safety database, follow-up information on the AE up to 30 days from the onset of 
the AE will also be included in the same database. Post-trial AEs not included in this 
database will be included in a separate pharmacovigilance database, which will be used for 
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Treatment-emergent adverse events (TEAEs) will be used for summary and analysis 
purposes. 
 
 
 
  All TEAEs will be coded by system organ classification and preferred terms 
according to version 15.0 of MedDRA®. 
 
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  
 
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. 
 


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Adverse events will be listed for all subjects, including verbatim and coded terms, duration, 
severity, and relationship to the study drug.  TEAE status will be determined based on the 
imputed dates as defined above. 
The incidence and proportion of subjects with TEAEs and SAEs will be summarized by 
System Organ Class and Preferred Term overall and by the Safety Groups defined in Section 
5.1.2. 
An overview of TEAEs will be provided that summarizes the incidence of subjects with one 
or more AE, the incidence of AEs by highest relationship, the incidence of AEs by highest 
severity, the incidence of AEs by action taken, the incidence of AEs outcome, the incidence 
of serious adverse events (SAEs), and the incidence of AEs by type of seriousness. 
The incidence and proportion of subjects with TEAEs and SAEs will also be summarized 
overall and by Safery Groups as follows: 
- 
TEAE by System Organ Class, and Preferred Term 
- 
TEAEs by Preferred Term, in descending order of frequency 
- 
TEAEs by highest severity 
- 
TEAEs by highest relationship 
- 
Treatment-related (defined as at least possibly related) TEAEs by System Organ 
Class, and Preferred Term 
- 
TEAEs resulting in discontinuation from the study 
- 
Treatment-related (defined as at least possibly related) TEAEs by System Organ 
Class, and Preferred Term, and severity 
- 
TEAEs by dose at time of onset 
- 
TEAEs by time of onset windows, where the denominator for each visit window is the 
total number of subjects with exposure to drug as of the first day of the window, 
defined as: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


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- 
Treatment Emergent SAE by System Organ Class and Preferred Term 
- 
Treatment Emergent Fatal SAE by System Organ Class and Preferred Term 
- 
Treatment-related SAE by System Organ Class, Preferred Term, and Severity 
TEAEs will also be summarized by subgroups as described in Section 6.4. 
 
6.3.2 Vital Signs 
Vital sign measurements (seated blood pressure, pulse rate, respiration rate, and temperature) 
at Visits 1, 3, 4, and 5 will be summarized using descriptive statistics (n, mean, standard 
deviation, median, minimum, maximum, and 95% CI). 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. 
Values considered clinically significant by the investigator are to be flagged. Criteria for 
possibly significant post-baseline changes are presented in Table 3. Number and percentages 
of subjects with post-baseline values of clinical significance will be summarized by visit. 
In addition, vital signs data will be listed for all subjects, inclusive of flags for whether the 
value is clinically significant in the investigator’s judgment and whether it meets pre-
specified criteria as being possibly clinically significant post-basesline. 
Vital sign values are considered as Possibly Clinically Significant (PCS) if they meet both the 
observed value criteria and the change from baseline criteria listed in Table 3 below. 
 
 
 
 
 


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Table 3: Possibly Clinically Significant Vital Sign Criteria 
 
The number and percentage of subjects with a PCS post-baseline vital sign value over all 
visits will be tabulated. Subjects with baseline and at least one post-baseline assessment will 
be included in the denominator and subjects who meet the PCS criteria at least once (based 
on all post-baseline assessments including unscheduled visits) will be included in the 
numerator. Subjects with a PCS post-baseline value will be flagged in the vital sign listing. 
 
6.3.3 Clinical Laboratory Tests 
The following tests will be performed at Screening (Week -2), Visit 5 (Week 26), and the 
Premature Termination visit (if applicable):  
• Hematology:  
• 
RBC, including RBC count and hemoglobin  
• 
Total WBC count  
• 
Differential WBC count  
• 
Platelet count  
 
• Serum chemistry: o  
• Sodium  
• 
Potassium  
• 
Chloride  
• 
BUN  
• 
Creatinine  
 
Clinical laboratory testing (hematology and chemistry) results at Visit 1 relative to Visit 5 
(Week 26) based on Conventional Units will be summarized using descriptive statistics (n, 
mean, standard deviation, minimum, median, maximum, and 95% CI).  Change from Visit 1 
to Visit 5 will also be summarized.  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. 
Values outside the laboratory normal range are to be flagged as L (low) and H (high). Shift 
tables displaying the shift from laboratory normal range between Visit 1 and Visit 5 will be 


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generated. Criteria for possibly significant changes for selected parameters appear in Tables 4 
and 5. The numbers and percentages of subjects meeting these criteria will be summarized by 
visit. 
 
Table 4: Possibly Clinically Significant Hematology Values 
 
 
 
Table 5: Possibly Clinically Significant Serum Chemistry Values 
 
 
The number and percentage of subjects with a PCS post-baseline laboratory value over all 
visits will be tabulated. Subjects with baseline and at least one post-baseline assessment will 
be included in the denominator and subjects who meet the PCS criteria at least once (based 
on all post-baseline assessments including unscheduled visits) will be included in the 
numerator. Subjects with a PCS post-baseline value will be flagged in laboratory listings. 
Clinical laboratory results will be listed for all subjects, inclusive of flags for whether or not 
the value is outside the laboratory normal range, considered significant by the investigator, or 
met the pre-specified criteria for being possibly clinically significant. 
 


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6.3.4 12-Lead ECG 
ECGs will be assessed at visit 1 (screening), visit 3 (week 4), visit 4 (week 12), and visit 5 
(week 26).  ECG measurements will be collected in triplicate 2 minues apart and read at the 
investigator site.  The following intervals will be collected: 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 1 (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. 
For the purposes of summary and analysis, results from the triplicate measurements at each 
visit will be averaged.  ECG results will be summarized by visit using counts and percentages 
for abnormalities noted by the investigator and T-wave abnormalities, and using descriptive 
statistics (n, mean, standard deviation, minimum, median, maximum, and 95% CI) for 
interval data.  For abnormality designations collected in triplicate, the worst outcome will be 
selected in the following order: Abnormal, Clinically Significant>Abnormal, Clinically Non-
Significant>Normal.  Any ECG abnormalities, based on clinical interpretation, will be 
reviewed for any emergent abnormalities that could be attributed to the new dosage form.  
Continuous ECG parameters will be summarized as change from Baseline (visit 1).  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. 
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 and Neurological Examinations 
Physical and neurological exminations will be performed at screening (visit 1) and week 26 
(visit 5). Normal and abnormal physical and neurological exam results will be summarized by 
visit, using counts and percentages. Physical and neurological examination findings will be 
listed. These will be reviewed for any emergent abnormalities that could be attributed to the 
new dosage form.  
 
6.3.6 Suicidality Assessment Using C-SSRS 
Results of the C-SSRS, assessed at each visit, will be evaluated and reported according to the 
Columbia Classification Algorithm of Suicide Assessment (C-CASA) for the Safety 
Population.
 
 
 
 
 
 


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6.4 Subgroup Analysis 
Subset analysis will be stratified by anti-spasticity and MS medications used (ie, tizanidine, 
fampridine, etc) at Visit 1 if the percentage of subjects in these stratification groups is ≥10% 
of the total number of subjects enrolled.  
 
The effects of any other medications and/or medical conditions present at Visit 1 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 stratified accordingly and the incidence of TEAEs in each 
part summarized.   
 
The incidence of TEAEsh will be summarized by the following subgroups: sex, age (below 
65 years of age and 65 years of age and older), and race. 
 


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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 the Clinical Data Management System 
(CDMS) database.  Further all tables, listings, and figures (TLFs) will undergo a QC process 
by an independent biostatistician/programmer to ensure that the information is complete, 
consistent with the analysis methods described in this SAP, and accurately reflects the data 
stored in CDMS.  
 
7.1 Programming Specifications for TLFs 
Appendix 1 provides a list of the TLFs that are planned to be produced. 
 
7.2 Formatting Conventions 
The following formatting conventions will be used to output TLFs:  
• TLFs 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, listing, or figure) will have the following header: 
 
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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/Listings/Figures 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., 
Safety Group 1 Subjects from Study Site 1, Safety Group 2 
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. 
 
 


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• Each line of a complete footnote should end with a period. 
• When an abbreviation (e.g. AE, SAE, etc.) appears for the first time in 
the whole set of TLFs 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 TLFs.  
• 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 – Listing 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), Minimum, Maximum, and N. In addition, 95% CI will be presented when 
appropriate.  
 
 
• Unless specified in the actual TLF shells for a study, all percentages will be rounded to 
2 decimal places in all tables/listings/figures, with the exception of adverse events, 


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which will be rounded to 1 decimal place.  Rounding will take place after all 
calculations have been performed. 
 
• 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 
Appendix 1: Subject Diary 
 
Appendix 2: Planned Tables, Listings, and Figures  
Table 14.1.1.1 
Screen Failure Summary 
Table 14.1.1.2 
Protocol Deviations – Safety Population 
Table 14.1.2 
Subject Disposition – Safety Population 
Table 14.1.3 
Demographics  – Safety Population 
Table 14.1.4 
Medical History – Safety Population 
Table 14.1.5.1 
Prior Medications – Safety Population 
Table 14.1.5.2.1 
Concomitant Medications – Safety Population 
Table 14.1.5.2.2 
Concomitant Medications – Anti-Spasticity -  Safety Population 
Table 14.1.5.2.3 
Concomitant Medications – Neurological - Safety Population 
Table 14.1.5.3 
Physical Therapy Regimens – Safety Population 
Table 14.1.6 
Physical Examination Results – Safety Population 
Table 14.1.7 
Neurological Examination Results – Safety Population 
Table 14.1.8.1.1 
Exposure Duration  – Safety Population 
Table 14.1.8.1.2 
Summary of Dosing by Dose Level and Visit – Safety Population  
Table 14.1.8.1.3 
Shift Table of Dosing by Dose Level and Visit – Safety Population 
 
Table 14.1.8.2.1 
 
Compliance – Safety Population 
Table 14.1.8.2.2 
Compliance as Assessed by Subject Diary – Safety Population 
Table 14.3.1.1 
Overview of Treatment-Emergent Adverse Events – Safety Population 
Table 14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term  – 
Safety Population 
Table 14.3.1.3 
Treatment-Emergent Adverse Events by Preferred Term  – Safety Population 
Table 14.3.1.4 
Treatment-Emergent Adverse Events by System Organ Classand Preferred Term by 
Sex – Safety Population 


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Table 14.3.1.5 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term by 
Age (<65 Years and ≥65 Years) – Safety Population  
Table 14.3.1.6 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term by 
Race – Safety Population 
Table 14.3.1.7.1 
Treatment-Emergent Adverse Events by System Organ Class, and Preferred Term by 
Medications Present in 20% or More of Overall Subjects at Visit 1  – Safety 
Population 
Table 14.3.1.7.2 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term by 
Medical Conditions Present in 20% or More of Overall at Visit 1 – Safety Population 
Table 14.3.1.7.3 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term by 
MS-Related Medications Taken by ≥ 10% of All Subjects at Visit 1 - Safety 
Population 
Table 14.3.1.8 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term and 
Severity – Safety Population  
Table 14.3.1.9.1 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term by 
Highest Relationship – Safety Population 
Table 14.3.1.9.2 
Treatment-Related Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term – Safety Population 
Table 14.3.1.9.3 
Treatment-Related Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Severity – Safety Population 
Table 14.3.1.10 
Treatment-Emergent Adverse Events Resulting in Discontinuation from the Study by 
System Organ Classand Preferred Term – Safety Population 
Table 14.3.1.11 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term by 
Dose at Time of Event – Safety Population 
Table 14.3.1.12 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term by 
Time of Onset Windows – Safety Population 
Table 14.3.2.1 
Treatment-Emergent Serious Adverse Events  by System Organ Class and Preferred 
Term  – Safety Population, Overall and by Safety Group 
Table 14.3.2.2 
Treatment-Emergent Fatal Serious Adverse Events by System Organ Class and 
Preferred Term – Safety Population 
Table 14.3.2.3 
Treatment-Related Treatment-Emergent Serious Adverse Events by System Organ 
Class, Preferred Term and Severity  – Safety Population 
Table 14.3.4.1.1 
Vital Sign Results – Safety Population 
Table 14.3.4.1.2 
Number and Percentage of Subjects with a Possibly Clinically Significant (PCS) Post-
Baseline Vital Sign Result, by Visit and Overall – Safety Population 
Table 14.3.4.2.1 
Hematology Assessments – Safety Population 
Table 14.3.4.2.2 
Hematology Shift Table – Safety Population 
Table 14.3.4.2.3 
Number and Percentage of Subjects with a Possibly Clinically Significant (PCS) Post-
Baseline Hematology Result, by Visit and Overall – Safety Population 
Table 14.3.4.3.1 
Serum Chemistry Assessments – Safety Population 
Table 14.3.4.3.2 
Serum Chemistry Shift Table – Safety Population 
Table 14.3.4.3.3 
Number and Percentage of Subjects with a Possibly Clinically Significant (PCS) Post-
Baseline Serum Chemistry Result, by Visit and Overall – Safety Population 
Table 14.3.4.4 
Electrocardiogram (ECG) Results – Safety Population 
Table 14.3.4.5.1 
Columbia Suicide Severity Rating Scale (C-SSRS) Results: Suicidal Ideation and 
Suicidal Behavior  
– Safety Population  
Table 14.3.4.5.2 
Columbia-Suicide Severity Rating Scale (C-SSRS): Suicidal Ideation and Behavior 
Overall During Trial – Safety Population 
 
 
Figure 14.1.2.1  
Subject Disposition – Safety Population 
Figure 14.3.4.5.1.1 
Columbia Suicide Severity Rating Scale (C-SSRS): Suicidal Ideation and Behavior 
Histogram – Safety Population 
 
 
Listing 16.2.1.1  
Subject Eligibility – Inclusion/Exclusion Criteria 


Sun Pharma Advanced Research Company, Ltd. 
Protocol CLR_11_04 
Statistical Analysis Plan 
 
 
Version 1.0 
 
 
 
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Listing 16.2.1.2 
Subject Disposition 
Listing 16.2.1.3 
Identification of Analysis Sets 
Listing 16.2.2 
Protocol Deviations  
Listing 16.2.4.1  
Demographics 
Listing 16.2.4.2.1 
Medical History 
Listing 16.2.4.2.2 
Surgical History  
Listing 16.2.4.2.3 
Spasticity and MS History 
Listing 16.2.4.2.4 
MS Symptoms Other Than Spasticity 
Listing 16.2.4.3.1 
Prior and Concomitant Medications 
Listing 16.2.4.3.2 
Neurological Concomitant Medications  
Listing 16.2.4.3.3 
Anti-Spasticity Concomitant Medications  
Listing 16.2.4.3.4 
Medications Used within 30 Days Prior to Screening 
Listing 16.2.4.3.5 
Physiotherapy Regimen 
Listing 16.2.4.4 
Baclofen History 
Listing 16.2.5.1.1 
Dose Administration 
Listing 16.2.5.1.2 
Dose Change, Sleep and Meal Information  
Listing 16.2.5.2 
Subject Diary 
Listing 16.2.7.1  
Adverse Events 
Listing 16.2.7.2  
Serious Adverse Events 
Listing 16.2.8.1  
Chemistry Laboratory Results 
Listing 16.2.8.2  
Hematology Laboratory Results 
Listing 16.2.8.3  
Urine Pregnancy Test Results 
Listing 16.2.9 
Vital Signs 
Listing 16.2.10.1 
Categorical 12-Lead ECG 
Listing 16.2.10.2 
Continuous 12-Lead ECG 
Listing 16.2.11  
Physical Examination 
Listing 16.2.12  
Neurological Examination