Clinical trial NCT03319732
Conditions: Multiple Sclerosis Spasticity, Muscle
Sponsor: RVL Pharmaceuticals, Inc.
Start date: 2018-04-03; Completion date: 2020-06-11
Enrollment: 323 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Spasticity is a common complication in MS and occurs in up to 84% of patients. The main sign of spasticity is resistance to passive limb movement characterized by increased resistance to stretching, clonus, and exaggerated deep reflexes. Osmotica Pharmaceutical is currently developing arbaclofen extended-release tablets (AERT) for the treatment of spasticity in patients with MS.

Detailed description:
This is a multicenter, open-label, long-term extension study to evaluate the safety and tolerability of oral AERT in patients with spasticity due to MS. Subjects from the double blind study (Study OS440-3004) may rollover into this open-label extension study, as well as de novo subjects. The maintenance dose will be 80 mg/day or the highest tolerated dose. Once the subject has reached the maintenance dose, they will remain on that dose for approximately 1 year.

Arms: arm 1: Arbaclofen extended release tablet, 20 mg
Interventions: intervention 1: Arbaclofen
Intervention descriptions: intervention 1: Arbaclofen is the active R enantiomer of baclofen.

Protocol documents:
SAP_002.pdf: 
COVER PAGE 
Document Type:  
 
Statistical Analysis Plan 
 
 
Document Name:  
 
An Open-Label Study to Evaluate the Long-Term Safety of Arbaclofen Extended-Release Tablets 
in Multiple Sclerosis Patients with Spasticity (Study OS3440-3005). 
 
 
NCT Number: 
 
NCT03319732 
 
 
Document Date: 
 
24 January 2020 




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1. 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ......................................................................................................................... 2 
2. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................... 5 
3. 
INTRODUCTION ................................................................................................................................... 6 
3.1. 
Preface ........................................................................................................................................ 6 
3.2. 
Purpose of Analyses .................................................................................................................... 6 
3.3. 
Summary of Statistical Analysis Changes to the Protocol ............................................................. 6 
4. 
STUDY OBJECTIVES AND ENDPOINTS............................................................................................. 7 
4.1. 
Study Objectives.......................................................................................................................... 7 
4.1.1. 
Primary Objective....................................................................................................... 7 
4.1.2. 
Secondary Objectives ................................................................................................. 7 
4.2. 
Study Endpoints .......................................................................................................................... 7 
4.2.1. 
Safety Endpoints ........................................................................................................ 7 
4.2.2. 
Efficacy Endpoints ..................................................................................................... 7 
5. 
STUDY METHODS ................................................................................................................................ 8 
5.1. 
General Study Design and Plan .................................................................................................... 8 
5.2. 
Randomization and Blinding ...................................................................................................... 13 
5.3. 
Analysis Variables ..................................................................................................................... 13 
6. 
SAMPLE SIZE ...................................................................................................................................... 13 
7. 
GENERAL CONSIDERATIONS .......................................................................................................... 13 
7.1. 
Analysis Populations ................................................................................................................. 13 
7.1.1. 
Screened Population (SCREEN) ............................................................................... 13 
7.1.2. 
Safety Population (SP) .............................................................................................. 14 
7.2. 
Covariates and Subgroups .......................................................................................................... 14 
7.2.1. 
Planned Covariates ................................................................................................... 14 
7.2.2. 
Planned Subgroups ................................................................................................... 14 
7.3. 
Management of Analysis Data ................................................................................................... 14 
7.3.1. 
Data Handling .......................................................................................................... 14 
7.3.2. 
Missing Data ............................................................................................................ 14 
7.3.2.1. 
Handling of Missing Date Values ......................................................... 14 
7.3.2.2. 
Imputation Methods ............................................................................. 15 
7.3.3. 
Handling of Early Termination Visit Information ...................................................... 15 
7.3.4. 
Pooling of Study Centers .......................................................................................... 15 
7.3.5. 
Coding Conventions for Events and Medications ...................................................... 15 
7.3.6. 
Analysis Software..................................................................................................... 15 
7.3.7. 
Study Data................................................................................................................ 16 
7.4. 
Planned Study Analyses ............................................................................................................. 17 
7.4.1. 
Statistical Summaries: Descriptive and Inferential..................................................... 17 
7.4.2. 
Interim Analyses and Data Monitoring...................................................................... 17 
7.4.3. 
Multiple Testing Procedures ..................................................................................... 17 
8. 
SUMMARY OF STUDY DATA ........................................................................................................... 18 
8.1. 
Subject Disposition .................................................................................................................... 18 
8.2. 
Protocol Deviations ................................................................................................................... 18 
8.3. 
Demographics and Baseline Characteristics ............................................................................... 18 
8.4. 
Medical and Surgical History ..................................................................................................... 18 


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8.5. 
Prior and Concurrent Medications .............................................................................................. 18 
8.6. 
Treatment Compliance ............................................................................................................... 19 
9. 
EFFICACY ANALYSES ....................................................................................................................... 20 
9.1. 
Efficacy Endpoints .................................................................................................................... 20 
9.2. 
Efficacy Analyses ...................................................................................................................... 20 
10. SAFETY ANALYSES ........................................................................................................................... 20 
10.1. 
Adverse Events .......................................................................................................................... 20 
10.2. 
Deaths, Serious Adverse Events and Other Significant Adverse Events ...................................... 21 
10.2.1. 
Deaths ...................................................................................................................... 21 
10.2.2. 
Serious Adverse Events ............................................................................................ 21 
10.2.3. 
Adverse Events Leading to Discontinuation of Study Drug ....................................... 21 
10.3. 
Clinical Laboratory Evaluations ................................................................................................. 22 
10.4. 
Vital Signs ................................................................................................................................. 22 
10.5. 
Physical Examinations ............................................................................................................... 22 
10.6. 
Other Safety Measures ............................................................................................................... 22 
11 
REPORTING CONVENTIONS............................................................................................................. 22 
11.1 
General Reporting Conventions ................................................................................................. 23 
11.2 
Population Summary Conventions ............................................................................................. 24 
12 
REVISION HISTORY ........................................................................................................................... 25 
 
 


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LIST OF TABLES 
 
Table 1 
Schedule of Assessments .......................................................................................... 11 
 
 
LIST OF FIGURES 
 
Figure 1 
Timeline Diagram....................................................................................................... 9 
Figure 2 
Flowchart of Open-Label Dosing Regimen ............................................................... 10 
Figure 3 
SDTM, ADaM, and TFL Development and Validation ............................................. 16 
 
 
 


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2. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Only abbreviations and terms relevant to the SAP are repeated herein. The reader is referred 
to the protocol for the complete and comprehensive list of abbreviations and definitions of 
terms for the study. 
Abbreviation 
Definition 
ADaM 
Analysis data Model 
AE 
Adverse event 
AERT 
Arbaclofen extended-release tablets 
CDISC 
Clinical Data Interchange Standards Consortium 
CRF 
Case report form 
C-SSRS 
Columbia–Suicide Severity Rating Scale 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDSS 
Expanded Disability Status Scale 
FDA 
Food and Drug Administration 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology (system) 
mAS 
Modified Ashworth Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MS 
Multiple Sclerosis 
PGIC 
Patient Global Impression of Change 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SDTM 
Study Data Tabulation Model 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TNmAS-MAL 
Total Numeric-Transformed Modified Ashworth Score – Most Affected Limb 
TNmAS-TL 
Total Numeric-Transformed Modified Ashworth Score – Total Limbs  
USP 
Urinary Symptom Profile - USP© questionnaire 
WHO 
World Health Organization 
WHO-DD 
World Health Organization – Drug Dictionary 
 
 


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3. 
INTRODUCTION 
3.1. 
Preface 
This document presents a statistical analysis plan (SAP) for Osmotica Pharmaceutical’s 
Protocol OS440-3005 (An Open-Label Study to Evaluate the Long-Term Safety of Arbaclofen 
Extended-Release Tablets in Multiple Sclerosis Patients with Spasticity). 
Reference materials for this statistical plan includes the protocol OS440-3005 (CLN.OS440-
3005.PR.A01Dated: 03 OCT 2017). 
The SAP described hereafter is an a priori plan.  The SAP will be finalized and approved 
prior to locking of the study database.     
For the reasons stated here, the conduct of the study in the field is considered to be 
independent of any study outcome that might materialize upon enactment of the currently 
proposed statistical plan.  
3.2. 
Purpose of Analyses 
The purposes of the planned analyses described in this SAP are to assess the safety and 
efficacy of oral arbaclofen extended-release tablets (AERT) in MS subjects with spasticity.  
Results from the analyses completed will be included in the final clinical study report for 
Study OS440-3005, and may also be utilized for regulatory submissions, manuscripts, or 
other clinical development activities. 
Post-hoc exploratory analyses not identified in this SAP may be performed to further 
examine the study data.  These analyses will be clearly identified, where appropriate, in the 
final clinical study report. Additional analyses not prospectively identified in this SAP may 
also be completed for publications, or regulatory or funding inquiries. These analyses, if 
performed, may not be reported in the clinical study report but will be fully documented in 
the document containing the additional analyses. 
3.3. 
Summary of Statistical Analysis Changes to the Protocol 
The analyses described in this analysis plan are consistent with the analyses described in the 
study protocol. 


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4. 
STUDY OBJECTIVES AND ENDPOINTS 
4.1. 
Study Objectives 
4.1.1. 
Primary Objective 
The primary objective of this study is to evaluate the long-term safety and tolerability of 
AERT in subjects with spasticity due to MS. 
 
4.1.2. 
Secondary Objectives 
The secondary objectives are to: 
• Assess the Patient Global Impression of Change (PGIC) over 1 year. 
• Assess the Total Numeric-transformed modified Ashworth Scale score of the most affected 
limb (TNmAS-MAL) over 1 year. 
• Assess the Expanded Disability Status Scale (EDSS) over 1 year. 
4.2. 
Study Endpoints 
4.2.1. 
Safety Endpoints 
Safety endpoints include the following: 
• Adverse events  
• Vital signs 
• Clinical laboratory tests 
• 12-lead electrocardiograms (ECGs) 
• Urinary Symptom Profile - USP© questionnaire (USP) 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
4.2.2. 
Efficacy Endpoints 
Efficacy endpoints include the following: 
• Patient Global Impression of Change (PGIC) 
• Total Numeric-Transformed Modified Ashworth Score – Most Affected Limb 
(TNmAS-MAL) 
• Total Numeric-Transformed Modified Ashworth Score – Total Limbs (TNmAS-TL) 
• Expanded Disability Status Scale (EDSS) 


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5. 
STUDY METHODS 
5.1. 
General Study Design and Plan 
As background for the statistical methods presented below, this section provides an overview 
of the study design and plan of study execution. The protocol is the definitive reference for 
all matters discussed in what follows. 
This is a multicenter, open-label, long-term extension study to evaluate the safety and 
tolerability of oral AERT in subjects with spasticity due to MS.  Subjects from the double-
blind study (Study OS440-3004) may rollover into this open-label extension study, as well as 
de novo subjects, provided that all inclusion and none of the exclusion criteria are met.   
Eligible de novo subjects will undergo an at least 21-day washout period for withdrawal of all 
medications used for anti-spasticity and/or muscle relaxation prior to enrolling in this open-
label study.  There will be a 9-day titration period, then a 52-week maintenance period, 
followed by a 2-week taper period.   
Figure 1 presents the timeline diagram for the study.  Figure 2 presents the open-label dosing 
regimen flowchart, including titration and taper doses, to be used during the study.  Once the 
subject has reached the maintenance dose, they will remain on that dose for approximately 1 
year.  The maintenance dose will be the highest tolerated dose not exceeding 80 arbaclofen mg 
per day.   
The schedule of assessments is presented in Table 1. 
 
 
 




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Figure 2 
Flowchart of Open-Label Dosing Regimen 
 
 
  
At the end of treatment, a 2-week taper period will take place from Weeks 54 to 56.  Subjects who discontinue early should also follow the 2-week taper 
period. 
 


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Table 1 
Schedule of Assessments 
Assessment or Procedure 
Baseline1 
Visits 
Final Visit2 
Study Visit 
(V6 of prior 
DB Study) 
1 
2 
3 
4 
5 
6 
7 
(telephone visit) 
8 
Study Week 
0 
(±3 days) 
2 
(±3 days) 
6 
(±5 days) 
14 
(±5 days) 
28 
(±5 days) 
42 
(±5 days) 
54 
(±3 days) 
56 
(±5 days) 
60 
(±3 days) 
Written informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
Withdrawal anti-spasticity medication 
X 
 
 
 
 
 
 
 
 
Assign enrollment number 
X 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
X 
 
 
 
X 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hematology/serum chemistry/urinalysis 
X 
 
X 
X 
X 
X 
X 
 
X 
Electrocardiogram 
X 
 
 
 
X 
 
 
 
X 
Pregnancy test4 
X 
X 
X 
X 
X 
X 
X 
 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
 
X 
TNmAS-MAL5 
X 
 
 
 
X 
 
 
 
X 
EDSS 
X 
 
 
 
X 
 
 
 
X 
PGIC6 
X 
 
 
 
X 
 
 
 
X 
USP© questionnaire 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dispense study medication 
X 
X 
X 
X 
X 
X 
X7 
 
 
Collect unused study medication 
 
X 
X 
X 
X 
X 
X 
 
X 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications/therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Schedule/confirm next study visit 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS = Columbia–Suicide Severity Rating Scale; DB = double-blind; EDSS = Expanded Disability Status Scale; FV = final visit; PGIC = Patient Global Impression of Change; 
TNmAS-MAL = Total Numeric-transformed modified Ashworth Scale score of the most affected limb; USP = Urinary Symptom Profile. 
 
(footnotes on next page) 


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Table 1 - Footnotes: 
1. Baseline for the study will be conducted at the same time as Visit 6/Day 92 (Final Visit) of Study OS440-3004 for subjects willing to continue into 
this study. All assessments performed at Visit 6/Day 92 (Final Visit) of Study OS440-3004 should not be repeated but should be recorded as the same 
assessments at Baseline for this study. 
Note:  For de novo subjects being considered for enrollment, a Screening visit (not shown in Table 1) should occur a maximum of 21 days prior to 
Baseline to allow for any concomitant medication wash-out required for Inclusion Criterion 6.  For de novo subjects, the first three procedures listed 
under Baseline (ie, informed consent, inclusion/exclusion criteria, and withdrawal of anti-spasticity medication) will be done at this Screening visit, 
as well as a serum pregnancy test (see footnote 4 below).  All other baseline assessments and procedures listed will be performed at the Baseline visit 
for de novo subjects. 
2. If a subject prematurely withdraws from the study, the subject should taper from study medication as described in Protocol Section 7.1 and all 
evaluations described under Visit 8/Week 60 (Final Visit) must be performed. 
3. Vital signs will be measured with the subject in a supine position and in a standing position 3 minutes after the supine assessment is completed.  Body 
temperature and respiratory rate will be measured only during the supine assessment. 
4. For de novo subjects, premenopausal women of childbearing potential must have a negative serum pregnancy test within 21 days before Baseline.  
Urine pregnancy testing will be performed for all female subjects at the other visits as noted. 
5. The TNmAS-MAL assessment will be performed prior to any scheduled lab draws.  The most affected limb will be determined by the investigator. 
6. The PGIC will not be done at Baseline for de novo subjects. 
7. At the end of treatment, a 2-week taper period will take place from Weeks 54 to 56.  Subjects who discontinue early should also follow the 2-week 
taper period. 


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5.2. 
Randomization and Blinding 
Not applicable, this is an open-label, non-randomized study. 
 
5.3. 
Analysis Variables 
Variables to be analyzed include demographics and baseline characteristics, safety variables 
(adverse events, vital signs, clinical laboratory investigations, ECGs, USP questionnaire, and 
C-SSRS), and efficacy variables (PGIC, TNmAS-MAL, TNmAS-TL, and EDSS). See 
Section 8 of the protocol for further details on the efficacy variables.  Derived variables from 
study endpoints are described with the sections describing the analyses for these endpoints. 
6. 
SAMPLE SIZE 
In total, approximately 300 subjects are to be enrolled in this study (ie, both rollover and de 
novo subjects).  It is anticipated that approximately 50% of subjects randomized into the 
double-blind study (Study OS440-3004) may rollover into this open-label study.  In the US 
only, up to 50 subjects may enroll into Study OS440-3005 without rolling over from Study 
OS440-3004.   
The number of subjects at each site will be determined primarily by the rate of recruitment in 
Study OSS440-3004.  No statistical rationale for subject number is provided.   
The sponsor has previously completed a 1-year, open-label safety study (Study OS440-3003 
using the 40-mg per day dose of arbaclofen. In Study OS440-3003 a total of 148 subjects 
were treated for 12 months. Study OS440-3005 is designed to enrich the existing safety 
database and provide long-term safety and tolerability data at the maximum daily dose of 80 
mg/day.  Target recruitment for Study OS440-3005 includes at least 100 subjects treated at 6 
months and 50 subjects treated for 1 year at 80-mg per day. 
7. 
GENERAL CONSIDERATIONS 
7.1. 
Analysis Populations 
There will be two (2) analysis populations defined for this study.  
7.1.1. 
Screened Population (SCREEN) 
Subjects who provide informed consent will be members of the screening population.  The 
screening population will include the total number of subjects who were considered for this 
study (rollover and de novo), regardless of participation. 


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7.1.2. 
Safety Population (SP) 
Includes all subjects who receive at least one dose of open-label study treatment and have at 
least one post-dose visit.  This population will be used for all safety and efficacy analyses. 
7.2. 
Covariates and Subgroups 
7.2.1. 
Planned Covariates 
No covariates are planned for this study. 
7.2.2. 
Planned Subgroups 
No subgroups are planned for this study. 
7.3. 
Management of Analysis Data 
7.3.1. 
Data Handling 
Unscheduled or repeated laboratory results will not be analyzed for the summary of 
continuous values but will be included in the laboratory shift tables as follows.  Unscheduled 
tests will be included with the time of the nearest regularly scheduled test.  If there is a 
scheduled test and one or more unscheduled tests assigned to the same time point, the most 
conservative test (i.e., a test with low or high results) will be used.  Repeated tests will be 
included only if they reflect abnormal (low or high) results and the corresponding original 
results are normal. All laboratory values, for all visits, will be provided in by subject listings. 
7.3.2. 
Missing Data 
In general, there will be no substitutions made to accommodate missing data points. All data 
recorded on the case report form (CRF) will be included in data listings that will accompany 
the clinical study report. 
7.3.2.1. 
Handling of Missing Date Values 
Partial or Missing Dates 
The following conventions will be used to impute missing portions of dates for adverse events 
and concomitant medications, if warranted.  Note that the imputed values outlined here may 
not always provide the most conservative date.  In those circumstances, the imputed value may 
be replaced by a date that will lead to a more conservative analysis. 
A. 
Start Dates 
1) 
If the year is unknown, then the date will not be imputed and will 
be assigned a missing value.  
2) 
If the month is unknown, then: 


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i) If the year matches the first dose date year, then impute 
the month and day of the first dose date. 
ii) Otherwise, assign ‘January.’  
3) 
 If the day is unknown, then: 
i) If the month and year match the first dose date month 
and year, then impute the day of the first dose date. 
ii) Otherwise, assign the first day of the month. 
B. 
Stop Dates 
1) 
If the year is unknown, then the date will not be imputed and will 
be assigned a missing value. 
2) 
If the month is unknown, then assign ‘December.’ 
3) 
If the day is unknown, then assign the last day of the month. 
 
7.3.2.2. 
Imputation Methods 
Observed cases, without imputation, will be used for of analyses.      
If the relationship of an AE is missing, it will be considered treatment-related. Missing AE 
severity will be coded as severe. 
7.3.3. 
Handling of Early Termination Visit Information 
If a subject is terminated early from this study the early termination visit data will be 
analyzed at the closest scheduled visit.  If the closest visit has valid data, the early 
termination data will be assigned to the next available visit. 
7.3.4. 
Pooling of Study Centers 
No pooling of study centers is planned for this study.   
7.3.5. 
Coding Conventions for Events and Medications 
All adverse events, and medical history will be mapped to the Medical Dictionary for 
Regulatory Activities (MedDRA Version 20.1) system for reporting (preferred term and body 
system).  Prior and concomitant medications will be coded using WHO-DD (Drug 
Dictionary) (Version September 2017). 
7.3.6. 
Analysis Software 
Data manipulation, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.4 or higher) for 
Windows.  If the use of other software is warranted, the final clinical study report will detail 
what software was used and for what purposes. 


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7.3.7. 
Study Data 
All study data will be formulated into regulatory compliant data sets to provide transparency, 
traceability, and integrity of trial analysis results from the collection source. Observed study 
data will be mapped to the CDISC Study Data Tabulation Model (SDTM) and serve as the 
source data from the trial.  All study analyses will be completed using analysis data sets that 
are derived from the SDTM and follow the CDISC Analysis Data Model (ADaM) 
architecture. All planned analyses will be performed using the ADaM data sets developed for 
this study. 
The methods for programming the CDISC SDTM and ADaM data sets are described in 
Figure 3. 
Figure 3 
SDTM, ADaM, and TFL Development and Validation 
 
Where: 
1. Development, Validation, and Maintenance of SDTM Domains 
2. Development and Validation of Analysis Data Sets (ADaM), with input source the 
appropriate SDTM domains. 
3. Development and Validation of Tables, Figures, and Listings (TFL), with input data 
source the analysis specific ADaM data sets. 
 


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7.4. 
Planned Study Analyses 
7.4.1. 
Statistical Summaries: Descriptive and Inferential 
No statistical tests will be performed in this study.   
Descriptive summaries of variables will be provided where appropriate.  For continuous 
variables, the number of non-missing values (n) and the median, mean, standard deviation, 
minimum, and maximum will be tabulated.  For categorical variables, the counts and 
proportions of each value will be tabulated.  Expansion of descriptive table categories may 
occur if such elaborations are thought to be useful. 
For the summary statistics of all numerical variables unless otherwise specified, minimum 
and maximum will be displayed to the same level of precision as reported. Mean and median 
will be displayed to one level of precision greater than the data collected. The standard 
deviation / standard error will be displayed to two levels of precision greater than the data 
collected. 
Change from baseline scores will be calculated as the post-baseline measurement minus the 
baseline value. 
Unless otherwise specified, all tables will be presented by Modal Dose of 40 mg, 60 mg, 
80 mg, and Overall group. 
All collected data will be presented in listings.  Data not subject to analysis according to this 
plan will not appear in any tables or figures but will be included in the data listings. 
7.4.2. 
Interim Analyses and Data Monitoring 
No formal interim analysis is planned for this study.  
A Data Safety Monitoring Board (DSMB) will oversee study subject safety with respect to 
AEs and clinically important lab values.  DSMB members will be independent of the 
Sponsor, study sites, and the managing vendors, and will have no other role in the trial.  
DSMB meetings for Study OS440-3005 will be scheduled after approximately 25% subjects 
have been randomized or 300 AEs (whichever comes first), 50% subjects have been 
randomized or 600 AEs (whichever comes first), 75% subjects have been randomized or 900 
AEs (whichever comes first) and 100% of subjects have been randomized. The DSMB 
Chairman will be responsible for determining a time for unscheduled meetings 
7.4.3. 
Multiple Testing Procedures 
Not applicable. 
 


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8. 
SUMMARY OF STUDY DATA 
8.1. 
Subject Disposition 
A summary of the analysis sets includes the number and percentage of subjects screened 
(rollover and de novo) and in the safety population. All percentages will be based on the 
number of subjects screened.  
End of trial information will also be summarized in this table, including the number of subjects 
completing the study and the number of subjects who prematurely discontinued the study with 
reasons for withdrawal. All percentages will be based on the number of subjects screened. 
A by-subject data listing of study completion information including the reason for premature 
study withdrawal, if applicable, will be presented. 
8.2. 
Protocol Deviations 
All protocol deviations will be presented in a data listing.  A summary table will also be 
generated based on the classification of protocol deviations. 
8.3. 
Demographics and Baseline Characteristics 
Subject demographic data and baseline characteristics will be tabulated and summarized 
descriptively.  Individual subject demographics and baseline characteristics will be provided 
in listings. 
8.4. 
Medical and Surgical History 
Medical and surgical history will be coded using the MedDRA Version 20.1. 
Subject medical and surgical history data including specific details will be presented in a 
listing. 
8.5. 
Prior and Concurrent Medications 
The number and percentages of all concomitant medications will be summarized, Anatomical 
Therapeutic Chemical (ATC) level 4 and PT.  The total number of concomitant medications 
and the number and percentages of subjects with at least 1 concomitant medication will be 
summarized. 
The number and percentages of all prior medications will be summarized similarly to 
concomitant medications in a separate table. 
A concomitant medication is defined as any medication taken on or after the day of first dose 
of study drug.  The prior medications are defined as any medication that starts and ends prior 
to the first dose of study drug.  


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8.6. 
Treatment Compliance 
The total number of days at each unique dose level and overall will be summarized. 
Dosing information, including date of administration, and days at each unique dose level will 
be listed by subject.  
 


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9. 
EFFICACY ANALYSES 
9.1. 
Efficacy Endpoints 
Efficacy endpoints include the following: 
• Patient Global Impression of Change (PGIC) 
• Total Numeric-Transformed Modified Ashworth Score – Most Affected Limb 
(TNmAS-MAL) 
• Total Numeric-Transformed Modified Ashworth Score – Total Limbs (TNmAS-TL) 
• Expanded Disability Status Scale (EDSS) 
 
9.2. 
Efficacy Analyses 
PGIC categories will be summarized by frequencies and percentages by study visit.  PGIC 
will also be summarized using descriptive statistics by study visit. 
TNmAS-MAL, TNmAS-TL, and EDSS will be summarized descriptively by study visit in 
terms of actual values and change from baseline values. In addition to this change from 
baseline (from Visit 6/ET in OS440-3004), the change from baseline in Study OS440-3004 
will be summarized for TNmAS-MAL and TNmAS-TL. 
10. 
SAFETY ANALYSES 
10.1. 
Adverse Events 
The number and percent of subjects with any treatment-emergent adverse events (TEAEs) 
will be displayed by system organ class and preferred term (MedDRA Version 20.1).  Within 
each preferred term, subjects will be counted only once if they had more than one event 
reported during the treatment period.   
TEAEs will also be summarized by greatest reported severity for each event preferred term.  
Counts indicate subjects reporting one or more TEAEs that map to the severity grade 
classification for each preferred term.  At each level of summarization (system organ class or 
event preferred term) subjects are only counted once and the worst severity case of repeated 
instances of the same TEAE will be used in tabulations.  TEAEs will also be summarized by 
strongest investigator assessment of relationship to study drug in a similar manner. 
In addition to the above described analyses, specific AE summaries will be presented under 
the following conditions: 
• TEAEs by SOC/PT will be presented by modal dose within period (titration/dose 
response, maintenance, and taper period). 


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• TEAEs by SOC/PT will be presented by dose the subject was on at time of event 
within period (titration/dose response, maintenance, and taper period). 
• All AE summaries will be presented by dose the subject was on at time of event. 
Analyses of AEs will be performed for those events that are considered treatment emergent, 
where treatment emergent is defined as any AE with onset or worsening on or after the first 
dose of study drug up until last dose of study drug.  
Treatment emergent summarization will be characterized by serious or not, the severity and 
the relationship with the study drug. A conservative approach will be taken to assess the 
relationship of an AE to study drug; if the relationship of an event is missing, it will be 
considered treatment-related. Missing severity will be coded as severe. 
All TEAEs will be listed individually by subject.  In addition, a separate listing will be 
produced for AEs that are not treatment-emergent.  
10.2. 
Deaths, Serious Adverse Events and Other Significant Adverse Events 
10.2.1. 
Deaths 
All deaths, regardless of causality, will be provided in listings and written clinical narratives. 
10.2.2. 
Serious Adverse Events 
The number and percent of subjects with Treatment Emergent Serious Adverse Event 
(TESAE) will be displayed by system organ class and preferred term, and relationship to 
study drug.  Within each preferred term, subjects will be counted only once if they had more 
than one TESAE event reported during the treatment period.  
Clinical narratives for each TESAE observed will be written to include important data and 
safety findings related to the individual TESAE and included in the final clinical study 
report. 
10.2.3. 
Adverse Events Leading to Discontinuation of Study Drug 
The number and percent of subjects with TEAE’s leading to discontinuation, or interruption, 
of study drug will be displayed by system organ class and preferred term.  Within each 
preferred term, subjects will be counted only once if they had more than one TEAE leading 
to discontinuation, or interruption, of study drug reported during the treatment period.  
A listing will be produced for all subjects who reported serious TEAEs or who discontinued 
study drug due to TEAEs. 


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10.3. 
Clinical Laboratory Evaluations 
Clinical Laboratory results will be summarized descriptively by time point for the observed 
value as well as for the change from baseline value.  In addition, laboratory shift tables will 
be provided for all laboratory parameters where low/normal/high or abnormal/normal status 
can be ascertained.   Listings of individual laboratory parameters by visit with normal ranges 
and abnormality assessments will also be completed by subject.   
10.4. 
Vital Signs 
Vital sign results will be summarized descriptively by time point for the observed value as 
well as for the change from baseline value.  All vital sign data by subject will be presented in 
a listing. Unscheduled visit results will not be summarized but will be included in subject 
data listings.  
10.5. 
Physical Examinations 
Physical examinations are conducted at baseline. A by subject listing will be completed to 
display all baseline physical examination information, as well as any optional PE information 
collected. 
10.6. 
Other Safety Measures 
C-SSRS results will be presented in subject data listings.   
USP summary scores (stress urinary incontinence score, overactive bladder score, and low 
stream score) will be summarized descriptively by time point for the observed value as well 
as for the change from baseline value.  All USP data (including the 10 individual questions) 
will be presented in listings. 
ECG parameters will be summarized descriptively by time point for the observed value as 
well as for the change from baseline value.  All ECG data will be presented in listings. 
No other safety analyses have been prospectively defined. If, however, after study results are 
reviewed, or the DSMB or Sponsor recommend additional safety parameters or analyses be 
completed, they will be fully described and documented in the final clinical study report. The 
SAP does not need to be amended to complete any other safety measures identified as post-
hoc. 
11 
REPORTING CONVENTIONS 
The following reporting conventions will be adopted for the presentation of study data.  
These conventions will enhance the review process and help to standardize presentation with 
common notations 


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11.1 
General Reporting Conventions 
• 
All tables and data listings will be developed in Landscape Orientation, unless 
presented as part of the text in a CSR. 
• 
Figures will be presented in Landscape Orientation, unless presented as part of 
the text in a CSR. 
• 
Legends will be used for all figures with more than one variable or item 
displayed. 
• 
Figures will be in presented in color with treatment groups distinguished by 
different symbols and colors.  Lines in figures should be wide enough to view 
the line after being photocopied.  
• 
Specialized text styles, such as bolding, italics, borders, shading, superscripted 
and subscripted text will not be used in tables, figures, and data listings unless 
they add significant value to the table, figure, or data listing.  
• 
Only standard keyboard characters should be used in tables and data listings. 
Special characters, such as non-printable control characters, printer specific, 
or font specific characters, will not be used on a table, figure, or data listing.  
Hexadecimal character representations are allowed (e.g.,µ,α,β). 
• 
All titles will be centered on a page.  The ICH numbering convention is to be 
used for all tables, figures, and data listings. 
• 
All footnotes will be left justified and the bottom of a page.  Footnotes must 
be present on the page where they are first referenced.  Footnotes should be 
used sparingly and must add value to the table, figure, or data listing.  If more 
than four footnote lines are planned then a cover page may be used to display 
footnotes. 
• 
Missing values for both numeric and character variables will be presented as 
blanks in a table or data listing.  A zero (0) may be used if appropriate to 
identify when the frequency of a variable is not observed. 
• 
All date values will be presented as YYYY-MM-DD (e.g., 2013-05-17) ISO 
8601 format. 
• 
All observed time values will be presented using a 24-hour clock HH:MM:SS 
format (e.g., 01:35:45 or 11:26).  Seconds should only be reported if they 
were measured as part of the study, also in ISO 8601 format. 
• 
Time durations will be reported in mixed HHh MMm SSs notation (e.g., 5h 
32m, or 27h 52m 31s).  The use of decimal notation to present (display) time 
durations should be avoided (e.g. 0.083h = 5m) unless it is necessary to show 
the computation of time differences in a table, figure, or data listing, in which 
case both notations may be used to display the time duration.  
• 
All tables, figures, and data listings will have the Table, Listing, or Graph 


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status (DRAFT, FINAL), and a date/time stamp on the bottom of each output.  
• 
All analysis programs developed for a table, figure, or data listing display will 
be self-contained to facilitate transfer of programs to multiple computing 
environments and transfer to a regulatory agency (if requested).  
• 
Study Number (Study OS440-3005) will be on every table, figure, or data 
listing display. 
11.2 
Population Summary Conventions 
• 
Population(s) represented on the tables or data listings will be clearly 
identified in the last title of the Table as “Population: <name of population>” 
and will be identical in name to that identified in the protocol or SAP. 
• 
Consistent terminology will be used to define and identify a population.   
• 
Sub-population(s) or special population(s) descriptions will provide sufficient 
detail to ensure comprehension of the population (e.g., FAS Females, Per-
Protocol Males >60 years of age) used for analysis in a table or figure. 
• 
Population sizes may be presented for each treatment or dosing category as 
totals in the column header as (N=xxxx), where appropriate.  
• 
Population sizes shown with summary statistics are the samples sizes (n) of 
subjects with non-missing values.  
• 
All population summaries for categorical variables will include all categories 
that were planned and for which the subjects may have had a response. 
Percentages corresponding to null categories (cells) will be suppressed.    
• 
All population summaries for continuous variables will include: N, mean, SD, 
minimum, and maximum.  Other summaries (e.g. number missing, median, 
quartiles, 5%, 95% intervals, CV or %CV) may be used as appropriate. 
• 
All percentages are rounded and reported to xx.x%. A percentage of 100% 
will be reported as 100%.  No value of 0% will be reported.  Any computation 
of percent that results in 0% is to be presented as a blank.  
• 
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 version) may be 
reported at the default level of precision.  P-values <0.0001 should be reported 
as <0.0001 not 0.0000. 
 


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12 
REVISION HISTORY 
Changes from version SAP.00:  The SAP was revised and amended to remove the 30 day 
window for the derivation of treatment emergent adverse events.  Adverse events will now be 
counted as treatment emergent up until the last dose date. 
Changes from version SAP.01: The SAP was revised and amended to add additional Adverse 
event analyses: All AE analyses by dose the subject was on at time of event; TEAEs by 
SOC/PT by modal dose and period (titration/dose response, maintenance, and taper period); 
TEAEs by SOC/PT analyses by dose the subject was on at time of event and period 
(titration/dose response, maintenance, and taper period). 
For TNmAS-MAL and TNmAS-TL, the baseline from OS440-3004 will be included as a 
separate analysis to the planned analyses using the baseline of Visit 6/ET result from Study 
OS440-3004. 
For dose exposure, the total days at each particular dose level have been added to the subject 
listing and a new summary table counting the total days at each dose level and overall has 
been included. 
For all tables modal dose categories have been changed from < 80 and = 80 mg to modal 
dose categories of 40 mg, 60 mg, and 80 mg. 

Prot_000.pdf: 
COVER PAGE 
Document Type:  
 
Study Protocol 
 
 
Document Name:  
 
An Open-Label Study to Evaluate the Long-Term Safety of Arbaclofen Extended-Release Tablets 
in Multiple Sclerosis Patients with Spasticity (Study OS3440-3005). 
 
 
NCT Number: 
 
NCT03319732 
 
 
Document Date: 
 
12 April 2018 






Study OS440-3005 
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Arbaclofen extended-release tablets 
 
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CONFIDENTIAL 
Page 3 of 70
 
Investigator Protocol Agreement 
Title:  An Open-Label Study to Evaluate the Long-Term Safety of Arbaclofen Extended-Release 
Tablets in Multiple Sclerosis Patients with Spasticity (Study OS440-3005) 
 
CONFIDENTIAL 
 
Document Number: CLN.OS440-3005.PR.A02.USA 
 
By my signature, I confirm that my staff and I have carefully read and understand this protocol or 
protocol amendment, and agree to comply with the conduct and terms of the study specified herein 
and with any other study conduct procedures provided by Osmotica Pharmaceutical or its 
designee.  For protocol amendments, I agree not to implement the amendment without agreement 
from the Sponsor and prior submission to and written approval (where required) from the 
Institutional Review Board (IRB), the Independent Ethics Committee (IEC), or their equivalent, 
and regulatory authority, except when necessary to eliminate an immediate hazard to the subjects, 
or for administrative aspects of the study (where permitted by all applicable regulatory 
requirements). 
 
 
 
Investigator’s Signature 
 
Date 
Name: 
 
 
Address:  
 
 
 
 
 
 
 
 


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Page 4 of 70
 
Table of Contents 
TITLE PAGE .....................................................................................................................1 
SIGNATURE PAGE ..........................................................................................................2 
INVESTIGATOR PROTOCOL AGREEMENT ...........................................................3 
TABLE OF CONTENTS ..................................................................................................4 
LIST OF IN-TEXT TABLES ...........................................................................................6 
LIST OF IN-TEXT FIGURES .........................................................................................6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................7 
1 
STUDY ADMINISTRATIVE STRUCTURE ..........................................................8 
2 
INTRODUCTION ......................................................................................................9 
2.1 
Multiple Sclerosis and Spasticity ..........................................................................9 
3 
STUDY OBJECTIVES ............................................................................................10 
3.1 
Primary Objective ................................................................................................10 
3.2 
Secondary Objectives...........................................................................................10 
4 
INVESTIGATIONAL PLAN ..................................................................................10 
4.1 
Overall Study Design ...........................................................................................10 
4.2 
Rationale for Study Design and Dose Selection ................................................10 
5 
STUDY POPULATION ...........................................................................................11 
5.1 
Inclusion Criteria .................................................................................................11 
5.2 
Exclusion Criteria ................................................................................................12 
6 
STUDY PROCEDURES ..........................................................................................13 
6.1 
Screening – De Novo Subjects Only ...................................................................17 
6.2 
Baseline – Visit 6 (Final Visit) of Study OS440-3004 (Week 0) .......................17 
6.3 
Visits 1, 2, 3, 5, and 6 – Weeks 2, 6, 14, 42, and 54 ............................................19 
6.4 
Visit 4 – Week 28 ..................................................................................................19 
6.5 
Visit 7 End of Taper (Telephone Visit) – Week 56 ...........................................20 
6.6 
Visit 8 (Final Visit or Early Termination) – Week 60 ......................................20 
7 
STUDY TREATMENTS ..........................................................................................21 
7.1 
Treatments Administered ...................................................................................21 
7.1.1 
Treatment Administration ............................................................................22 
7.1.2 
Labeling of Study Drug .................................................................................22 
7.1.3 
Storage of Study Drug ...................................................................................22 
7.2 
Study Drug Accountability..................................................................................23 
7.3 
Handling and Disposal of Study Drug ...............................................................23 
7.4 
Method of Assignment of Study Drug ................................................................23 
7.5 
Selection and Timing of Doses in the Study.......................................................24 
7.6 
Emergency Unblinding ........................................................................................26 
7.7 
Prior and Concomitant Therapy ........................................................................26 
7.8 
Use of Contraception and Pregnancy Testing ...................................................27 
7.9 
Treatment Compliance ........................................................................................28 
8 
EFFICACY ASSESSMENTS ..................................................................................28 
8.1 
Patient Global Impression of Change ................................................................28 
8.2 
Total Numeric-Transformed Modified Ashworth Scale ..................................28 
8.3 
Expanded Disability Status Scale .......................................................................29 
9 
SAFETY ASSESSMENTS .......................................................................................30 


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9.1 
Medical/Surgical History.....................................................................................30 
9.2 
Vital Signs .............................................................................................................30 
9.3 
Physical Examination ..........................................................................................30 
9.4 
Weight and Height ...............................................................................................31 
9.5 
Clinical Laboratory Tests....................................................................................31 
9.6 
Other Safety Assessments....................................................................................32 
9.6.1 
Electrocardiograms........................................................................................32 
9.6.2 
Urinary Symptom Profile© Questionnaire...................................................32 
9.6.3 
Columbia–Suicide Severity Rating Scale .....................................................32 
9.7 
Adverse Events .....................................................................................................33 
9.7.1 
Method of Determining Adverse Events ......................................................33 
9.7.2 
Adverse Event Definitions .............................................................................33 
9.7.2.1 
Adverse Events .........................................................................................33 
9.7.2.2 
Serious Adverse Events ...........................................................................34 
9.7.2.3 
Severity of Adverse Events ......................................................................34 
9.7.2.4 
Relationship of Adverse Events to Study Treatments ..........................35 
9.7.2.5 
Adverse Events Expectedness .................................................................35 
9.7.3 
Reporting Adverse Events .............................................................................35 
9.7.4 
Adverse Event Follow-Up..............................................................................36 
9.7.5 
Pregnancy Reporting .....................................................................................36 
9.8 
Appropriateness of Safety Measurement ...........................................................37 
10 DATA SAFETY MONITORING BOARD ............................................................37 
11 STATISTICAL DESIGN AND ANALYSIS ..........................................................37 
11.1 
Statistical Analysis Plans .....................................................................................37 
11.2 
Analysis Populations ............................................................................................37 
11.3 
Determination of Sample Size .............................................................................37 
11.4 
Efficacy Analyses .................................................................................................38 
11.4.1 
Efficacy Endpoints .........................................................................................38 
11.4.1.1 
Patient Global Impression of Change ....................................................38 
11.4.1.2 
Total Numeric-Transformed Modified Ashworth Scale ......................38 
11.4.1.3 
Expanded Disability Status Scale ...........................................................38 
11.5 
Safety Endpoints ..................................................................................................38 
11.6 
Interim Analysis ...................................................................................................39 
12 STUDY MANAGEMENT........................................................................................39 
12.1 
Monitoring ............................................................................................................39 
12.2 
Protocol Amendments .........................................................................................39 
12.3 
Protocol Deviations ..............................................................................................40 
12.4 
Withdrawal of Subjects .......................................................................................40 
12.5 
Termination of the Study ....................................................................................41 
12.6 
Publication Policy.................................................................................................41 
13 ETHICS .....................................................................................................................41 
13.1 
Conduct of the Study ...........................................................................................41 
13.2 
Institutional Review Boards and/or Independent Ethics Committees ............41 
13.3 
Written Informed Consent ..................................................................................42 
13.4 
Subject Confidentiality ........................................................................................42 
13.5 
Records Retention ................................................................................................42 


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13.6 
Financing ..............................................................................................................43 
14 QUALITY CONTROL AND QUALITY ASSURANCE ......................................43 
15 DATA HANDLING AND RECORD KEEPING...................................................43 
16 REFERENCE LIST..................................................................................................45 
APPENDIX 1. 
MODIFIED ASHWORTH SCALE .................................................46 
APPENDIX 2. 
EXPANDED DISABILITY STATUS SCORE ...............................47 
APPENDIX 3. 
PATIENT GLOBAL IMPRESSION OF CHANGE SCALE ........49 
APPENDIX 4. 
COLUMBIA–SUICIDE SEVERITY RATING SCALE ................50 
C-SSRS – Baseline/Screening Version ...........................................................................50 
C-SSRS – Since Last Visit Version .................................................................................55 
APPENDIX 5. 
PROHIBITED CONCOMITANT MEDICATION LIST ..............60 
APPENDIX 6. 
URINARY SYMPTOM PROFILE QUESTIONNAIRE ...............61 
APPENDIX 7. 
 SAFETY REPORTING LINES ...66 
APPENDIX 8. 
SUMMARY OF CHANGES .............................................................69 
 
List of In-Text Tables 
Table 1: 
Schedule of Assessments, Study OS440-3005 ........................................14 
Table 2: 
Study Drug Kits and Treatments, Study OS440-3005 ..........................22 
Table 3: 
Taper and Washout Periods for Specific Anti-spasticity and/or 
Muscle Relaxation Medications, Study OS440-3005 ............................26 
Table 4: 
Clinical Laboratory Tests, Study OS440-3005 ......................................31 
 
List of In-Text Figures 
Figure 1: 
Timeline Diagram, Study OS440-3005 ...................................................16 
Figure 2: 
Flowchart of Open-Label Dosing Regimen, Study OS440-3005 ..........25 
 
 
 
 


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List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
AE 
Adverse event 
AERT 
Arbaclofen extended-release tablets 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
BID 
Twice daily 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CNS 
Central nervous system 
CRO 
Contract Research Organization 
C-SSRS 
Columbia–Suicide Severity Rating Scale 
DSMB 
Data Safety Monitoring Board 
DSS 
Disability Status Scale 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDSS 
Expanded Disability Status Scale 
FDA 
Food and Drug Administration 
FS 
Functional system 
GCP 
Good Clinical Practices 
GFR 
Glomerular filtration rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LUTS 
Lower urinary tract symptoms 
mAS 
Modified Ashworth Scale 
MDRD 
Modification of Diet in Renal Disease Study 
MedDRA 
Medical Dictionary for Regulatory Activities 
MS 
Multiple sclerosis 
NARCOMS 
North American Research Committee on MS 
NIMH 
National Institute of Mental Health 
PGIC 
Patient Global Impression of Change 
PT 
Preferred term 
RBC 
Red blood cell 
RDC 
Remote data capture 
ROM 
Range of movement 
RR 
Relapsing-remitting (MS) 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SOC 
System organ class 
SP 
Secondary-progressive (MS) 
TEAE 
Treatment-emergent adverse event 
TNmAS-MAL 
Total Numeric-transformed mAS score of the most affected limb 
US 
United States 
USP 
Urinary Symptom Profile – USP© questionnaire 
WBC 
White blood cell 
WHO 
World Health Organization 


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1 
STUDY ADMINISTRATIVE STRUCTURE 


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2 
INTRODUCTION 
2.1 
Multiple Sclerosis and Spasticity 
Multiple sclerosis (MS) is an acquired inflammatory demyelinating disease of the central nervous 
system (CNS) that is regarded as the foremost cause of non-traumatic neurologic disability in 
adults in North America.  Multiple sclerosis has a prevalence of approximately 1 case per 1,000 in 
the population and a predominance in women (female to male ratio, 2:1).  The mean age at onset 
is 30 years.  Although MS is a heterogeneous illness, in 85% of patients it begins with episodic, 
largely reversible neurologic dysfunction, in a pattern termed relapsing-remitting (RR) MS.  In 
75% of those patients, the disease advances over time to a steady, irreversible worsening state 
designated secondary-progressive (SP) MS.  Less than 5% of patients have very severe disability 
(fulminant MS) within the first 5 years after onset, and 10% to 20% of patients remain unimpaired 
without therapy (benign MS) for 20 years or so. 
Clinical manifestations of MS include visual loss, paresthesias, weakness, spasticity, fatigue, and 
pain.  Multiple sclerosis symptoms may initially wax and wane with the onset and resolution of 
exacerbations.  However, in the latter disease stages, most patients progress to have some 
permanent disability.  Multiple sclerosis treatment relies on pharmaceutical agents to slow disease 
progression and reduce the burden of MS symptoms. 
Spasticity is a common complication in MS and occurs in up to 84% of patients.  The main sign 
of spasticity is resistance to passive limb movement characterized by increased resistance to 
stretching, clonus, and exaggerated deep reflexes.  The associated features of spasticity, including 
pain, gait disorders, fatigue, and loss of function, significantly affect patient quality of life.  Data 
collected from the North American Research Committee on MS (NARCOMS) Patient Registry 
showed that 34% of over 20,000 MS patients surveyed experienced moderate, severe, or total 
limitation of physical abilities due to spasticity.  Consequently, one of the main objectives for the 
functional management of MS is the symptomatic treatment of spasticity, aiming to improve gait, 
hygiene, and all the impeded activities of daily living.  However, current oral pharmacologic 
treatments of MS fail in the total control of this problem, both for intolerability or lack of efficacy, 
defining the unmet medical need for treatment of spasticity. 
Baclofen has been in clinical use for more than 35 years and the benefits and risks are well 
characterized.  It is approved for the treatment of spasticity due to MS and spinal cord injury and 
is a first-line pharmacotherapy as described in the MS Council for Clinical Practice Guidelines for 
treatment of spasticity in MS.  However, the therapeutic potential of baclofen is limited because it 
is poorly tolerated by patients due to the side effects of sedation, drowsiness, and worsening of 
fatigue.  Therefore, an unmet medical need exists for an effective, better tolerated oral treatment 
of spasticity. 
Baclofen is a racemate (rac-baclofen) consisting of an equal mixture of two enantiomers:  the l- or 
R-enantiomer (arbaclofen) and the d- or S-enantiomer. 
Osmotica Pharmaceutical is currently developing arbaclofen extended-release tablets (AERT) for 
the treatment of spasticity in patients with MS.  Arbaclofen is the active R-enantiomer of baclofen 
and it has been postulated that the efficacy of baclofen is primarily due to the R-enantiomer.  This 


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clinical study is an open-label extension of the Phase 3 double-blind Study OS440-3004 to 
evaluate the long-term safety and tolerability of AERT in patients with spasticity due to MS. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to evaluate the long-term safety and tolerability of AERT in 
patients with spasticity due to MS. 
3.2 
Secondary Objectives 
The secondary objectives are to: 
• Assess the Patient Global Impression of Change (PGIC) over 1 year. 
• Assess the Total Numeric-transformed modified Ashworth Scale score of the most affected 
limb (TNmAS-MAL) over 1 year. 
• Assess the Expanded Disability Status Scale (EDSS) over 1 year. 
4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is a multicenter, open-label, long-term extension study to evaluate the safety and tolerability 
of oral AERT in patients with spasticity due to MS.  Subjects from the double-blind study 
(Study OSS440-3004) may rollover into this open-label extension study, as well as de novo 
subjects, provided that all inclusion and none of the exclusion criteria are met.  Eligible de novo 
subjects will undergo a washout period withdrawing all medications used for anti-spasticity and/or 
muscle relaxation up to 21 days prior to enrolling in this open-label study.  There will be a 9-day 
titration period, then a 52-week maintenance period, followed by a 2-week taper period.  Figure 1 
presents the timeline diagram for the study.  Figure 2 presents the open-label dosing regimen 
flowchart, including titration and taper doses, to be used during the study.  Once the subject has 
reached the maintenance dose, they will remain on that dose for approximately 1 year.  The 
maintenance dose will be the highest tolerated dose not exceeding 80 mg per day.  Table 1 presents 
the schedule of assessments, including study visits and weeks, for the study. 
4.2 
Rationale for Study Design and Dose Selection 
Chronic exposure in an open-label extension design is appropriate to evaluate the safety of 
long-term use of an investigational product.  The omission of a control group is appropriate.  The 
subjects will be selected according to predefined entry criteria from the previous Phase 3, 
randomized, multicenter, double-blind, placebo-controlled study.  The open-label study treatment 
duration of approximately 1 year is adequate for chronic exposure.  Nonclinical arbaclofen data 
from a 3-month rat toxicity study (Study 0460RO24.001) show margins of exposure greater than 
1 and adverse effects at exposures up to 10-fold higher than those projected to occur in this Phase 
3 study that were not life-threatening, were clinically monitorable, and were reversible, which 


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supports a dose level of 80 mg.  To date, Osmotica has conducted 11 clinical studies (Phases 1 
through 3) utilizing AERT in doses up to 80 mg/day in single and divided doses. 
The open-label extension study is necessary to obtain safety information about the long-term use 
of AERT at the highest target dose to treat patients with spasticity due to MS because it is a chronic 
condition. 
5 
STUDY POPULATION 
It is anticipated that approximately 50% of subjects randomized into the double-blind study 
(Study OSS440-3004) may rollover into this open-label study.  In addition, United States (US) 
subjects who did not participate in Study OS440-3004 (i.e., de novo subjects) may also enroll into 
the current study provided that all inclusion and none of the exclusion criteria are met.  In total, 
approximately 300 subjects are to be enrolled in order to achieve treatment of at least 100 subjects 
for 6 months, and 50 subjects at 80 mg/day for at least 1 year; however, the sponsor reserves the 
right to end this clinical study after a sufficient number of subjects have enrolled to complete the 
requirement. 
5.1 
Inclusion Criteria 
Male and female subjects will be considered eligible for participation in the study if all the 
following inclusion criteria are satisfied at Visit 1 (Baseline). 
1. Subjects 18 to 65 years of age, inclusive. 
2. An established diagnosis per McDonald Criteria (Polman et al 2011) of MS (either RR or 
SP course) that manifests a documented history of spasticity for at least 6 months prior to 
Baseline. 
3. Has participated in Study OS440-3004 or is a new US subject (i.e., a de novo subject) who 
fulfills the inclusion/exclusion criteria. 
a. De novo subjects being considered for enrollment must have spasticity due to MS as 
shown by a TNmAS-MAL score ≥2a (Appendix 1) 
4. Is willing to continue on open-label treatment with AERT as described in this protocol. 
5. If receiving disease-modifying medications (e.g., interferons approved for MS, glatiramer 
acetate, natalizumab, fingolimod, or mitoxantrone), there must be no change in dose for at 
least 3 months prior to Baseline, and the subject must be willing to maintain this treatment 
dose for the duration of the study.  If receiving AMPYRA® (dalfampridine, fampridine, 
4-amino puridine), subject must be at a stable dose for at least 3 months prior to Baseline. 
6. Stable regimen for at least 1 month prior to Baseline for all medications and 
non-pharmacological therapies that are intended to alleviate spasticity. 
                                                 
a Total numerical score of a limb accounts for the sum of the 3 main joint muscular group scores. 


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a. De novo subjects being considered for enrollment and taking medications indicated for 
the treatment of spasticity (i.e., baclofen, benzodiazepines, cannabinoids, carisoprodol, 
dantrolene, tizanidine, cyclobenzaprine, any neuroleptic, ropinoprole, tolperisone, and 
clonidine) must wash out from these medications for at most 21 days by Baseline in 
order to be eligible for study treatment.  De novo subjects found not to meet this 
criterion will be withdrawn from the study and will be considered screen failures. 
7. Absence of infections, peripheral vascular disease, painful contractures, advanced arthritis, 
or other conditions that hinder evaluation of joint movement. 
8. Creatinine clearance, as calculated by the glomerular filtration rate (GFR) using the 
Modification of Diet in Renal Disease Study (MDRD) formula,b of >50 mL/minute. 
9. Use of a medically highly effective form of birth control (see Section 7.8) during the study 
and for 3 months thereafter for women of child-bearing potential (including female 
subjects). 
10. Willing to sign the informed consent form (ICF). 
5.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will not qualify for the study. 
1. Any concomitant disease or disorder that has symptoms of spasticity or that may influence 
the subject’s level of spasticity. 
2. Inability to rate their level of spasticity or distinguish it from other MS symptoms. 
3. Use of high dose oral or intravenous methylprednisolone, or equivalent, within 3 months 
before Baseline. 
4. History of allergy to baclofen or any inactive components of the test formulation. 
5. Concomitant use of medications that would potentially interfere with the actions of the 
study medication or outcome variables (Appendix 5). 
6. Pregnancy, lactation, or planned pregnancy during the course of the study and for 3 months 
after the final study visit. 
7. Recent history (within past 12 months) of any unstable psychiatric disease (or yes response 
to questions 1 or 2 on the Columbia Suicide Severity Rating Scale [C-SSRS] at baseline), 
or current signs and symptoms of significant medical disorders such as severe, progressive, 
                                                 
b GFR Calculator: 
 
GFR (mL/min/1.73 m2) = 175 x (Scr (mg/dL))-1.154 x (Age (years))-0.203 x (0.742 if female) x (1.212 if 
African American) (conventional units) 
 
GFR (mL/min/1.73 m2) = 175 x (Scr (µmol/L)/88.4)-1.154 x (Age (years))-0.203 x (0.742 if female) x (1.212 
if African American) (SI units) 
 


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or uncontrolled pulmonary, cardiac, gastrointestinal, hepatic, renal, genitourinary, 
hematological, endocrine, immunologic, or neurological disease. 
8. History of epilepsy. 
9. Current significant cognitive deficit, severe or untreated anxiety, severe or untreated 
depression. 
10. Subjects with abnormal micturition that requires indwelling or intermittent catheterization 
or with lower urinary tract symptoms (LUTS) that result in a score >26 in the Baseline 
Urinary Symptom Profile – USP© (USP) questionnaire (Appendix 6).  Subjects who are 
proficient in self-catheterization may be included in the study at the investigator’s 
discretion. 
11. Current malignancy or history of malignancy that has not been in remission for more than 
5 years, except effectively treated basal cell skin carcinoma. 
12. Subject has clinically significant abnormal laboratory values, in the opinion of the 
investigator at Screening (at Visit 6 for rollover subjects). 
13. Any other significant disease, disorder, or significant laboratory finding, including 
clinically significant abnormal laboratory values or ongoing serious adverse events (SAEs) 
at Visit 6 (Final Visit) of Study OS440-3004, which, in the opinion of the investigator, puts 
the subject at risk because of participation, influences the result of the study, or affects the 
subject’s ability to participate. 
14. Planned elective surgery or other procedures requiring general anesthesia during the course 
of the study. 
15. History of any illicit substance abuse (e.g., alcohol, marijuana, cocaine) or prescription for 
long-acting opioids within the past 12 months (tramadol use will be allowed). 
16. Participation in another clinical research study (with the exception of Study OS440-3004) 
within 1 month of Baseline. 
6 
STUDY PROCEDURES 
Table 1 and the following subsections present the planned study visits, timing, and details for study 
procedures.  Figure 1 presents the timeline diagram for the study.  The flowchart depicting the 
open-label dosing schema for this study is presented in Figure 2. 
 
 


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Table 1: 
Schedule of Assessments, Study OS440-3005 
Assessment or Procedure 
Screening1 
Baseline1 
Baseline1 
Visits 
Final 
Visit2 
Study Visit 
De Novo 
subjects 
only 
De Novo 
subjects 
only 
(V6 of prior 
DB Study) 
1 
2 
3 
4 
5 
66 
7 
(telephone visit) 
8 
Study Week 
up to 21 
days before 
Baseline  
0 
(±3 days) 
0 
(±3 days) 
2 
(±3 
days) 
6 
(±5 
days) 
14 
(±5 
days) 
28 
(±5 
days) 
42 
(±5 
days) 
54 
(±3 
days) 
56 
(±5 days) 
60 
(±3 
days) 
Written informed consent 
X 
 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
X 
 
 
 
 
 
 
 
 
Withdrawal anti-spasticity medication 
X 
 
X 
 
 
 
 
 
 
 
 
Assign enrollment number 
 
X 
X 
 
 
 
 
 
 
 
 
Demography 
X 
 
X 
 
 
 
 
 
 
 
 
Medical/surgical history; physical 
examination; height 
X 
 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
X 
 
 
 
X 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hematology/serum chemistry/urinalysis 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Electrocardiogram 
X 
 
X 
 
 
 
X 
 
 
 
X 
Pregnancy test4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
TNmAS-MAL5 
X 
X 
X 
 
 
 
X 
 
 
 
X 
EDSS 
X 
 
X 
 
 
 
X 
 
 
 
X 
PGIC 
 
X 
X 
 
 
 
 
 
 
 
X 
USP© questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dispense study medication 
 
X 
X 
X 
X 
X 
X 
X 
X6 
 
 
Collect unused study medication 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
Adverse event assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications/therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Schedule/confirm next study visit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS = Columbia–Suicide Severity Rating Scale; DB = double-blind; EDSS = Expanded Disability Status Scale; FV = final visit; PGIC = Patient Global 
Impression of Change; TNmAS-MAL = Total Numeric-transformed modified Ashworth Scale score of the most affected limb; USP = Urinary Symptom Profile 
(footnotes on next page) 


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Table 1 - Footnotes: 
1. Baseline for the study will be conducted at the same time as Visit 6/Day 92 (Final Visit) of Study OS440-3004 for subjects willing to continue into this study. 
All assessments performed at Visit 6/Day 92 (Final Visit) of Study OS440-3004 should not be repeated but should be recorded as the same assessments at 
Baseline for this study. 
Note:  For de novo subjects being considered for enrollment, a Screening visit should occur a maximum of 21 days prior to Baseline to allow for any concomitant 
medication wash-out required for Inclusion Criterion 6.  For de novo subjects, only the following assessments and procedures will be performed at the Baseline 
visit: assign enrollment number, vital signs, urine pregnancy test, C-SSRS, TNmAS-MAL, PGIC, USP, dispensing of study medication, recording of AEs and 
concomitant medications, and scheduling/confirmation of the next study visit.  
2. If a subject prematurely withdraws from the study, the subject should taper from study medication as described in Section 7.1 and all evaluations described 
under Visit 8/Week 60 (Final Visit) must be performed. 
3. Vital signs will be measured with the subject in a supine position and in a standing position 3 minutes after the supine assessment is completed.  Body temperature 
and respiratory rate will be measured only during the supine assessment. 
4. For de novo subjects, premenopausal women of childbearing potential must have a negative serum pregnancy test within 21 days before Baseline.  Urine 
pregnancy testing will be performed for all female subjects at the other visits as noted. 
5. The TNmAS-MAL assessment will be performed prior to any scheduled laboratory draws.  The most affected limb will be determined by the investigator. 
6. At the end of treatment, a 2-week taper period will take place from Weeks 54 to 56.  Subjects who discontinue early should also follow the 2-week taper period. 




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6.1 
Screening – De Novo Subjects Only 
For de novo subjects being considered for enrollment, a Screening visit (shown in Table 1) should 
occur a maximum of 21 days prior to Baseline to allow for any concomitant medication wash-out 
required for Inclusion Criterion 6.  For de novo subjects, the following procedures will be done at 
this Screening visit:  
• Obtain a signed and dated ICF from each subject prior to any study-specific procedures being 
conducted (Section 13.3). 
• Assess eligibility according to the inclusion (Section 5.1) and exclusion criteria (Section 5.2). 
• After establishing the subject’s eligibility to participate, explain to de novo subjects how to 
withdraw all anti-spasticity medication (up to a 21-day period) prior to the next visit. 
• Record demographic data, including age, sex, race, and ethnicity.  
• Record medical and surgical history (Section 9.1). 
• Record physical examination results (Section 9.3). 
• Record weight and height (Section 9.4). 
• Record vital sign measurements, including blood pressure (BP), heart rate, respiratory rate, 
and body temperature (Section 9.2). 
• Collect blood and urine samples for hematology, serum chemistry, and urinalysis (Section 9.5).  
Subject should be fasting if possible.  
• Perform a standard 12-lead electrocardiogram (ECG) (Section 9.6.1). 
• Collect a sample to perform a serum pregnancy test (Section 7.8). 
• Administer the Columbia–Suicide Severity Rating Scale (C-SSRS) (Section 9.6.3). 
• Perform the TNmAS-MAL assessment (Section 8.2). 
• Administer the EDSS assessment (Section 8.3). 
• Administer the USP questionnaire (Section 9.6.2). 
• Record all concomitant medications/therapies the subject is currently taking (Section 7.7). 
6.2 
Baseline – Visit 6 (Final Visit) of Study OS440-3004 (Week 0) 
For de novo subjects, the following assessments and procedures will be performed at the Baseline 
visit: assign enrollment number, vital signs, urine pregnancy test, C-SSRS, TNmAS-MAL, PGIC, 


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USP, dispensing of study medication, recording of AEs and concomitant medications, and 
scheduling/confirmation of the next study visit. 
For Study OS440-3004 subjects willing to continue into this study, Baseline for this study will be 
conducted at the same time as Visit 6/Day 92 (Final Visit) of Study OS440-3004. All assessments 
performed at Visit 6/Day 92 (Final Visit) of Study OS440-3004 should not be repeated but should 
be recorded as the same assessments at Baseline for this study. 
At Baseline, the investigator will fully explain to the subject the objectives, characteristics, and 
procedures for the open-label study.  Baseline assessments/procedures will include the following: 
• Obtain a signed and dated ICF from each subject prior to any study-specific procedures being 
conducted (Section 13.3). 
• Assess eligibility according to the inclusion (Section 5.1) and exclusion criteria (Section 5.2). 
• Assignment of an enrollment number (Section 7.4). 
• Record demographic data, including age, sex, race, and ethnicity. 
• Record medical and surgical history (Section 9.1). 
• Record physical examination results (Section 9.3). 
• Record weight and height (Section 9.4). 
• Record vital sign measurements, including blood pressure (BP), heart rate, respiratory rate, 
and body temperature (Section 9.2). 
• Collect blood and urine samples for hematology, serum chemistry, and urinalysis (Section 9.5).  
Subject should be fasting if possible. 
• Perform a standard 12-lead electrocardiogram (ECG) (Section 9.6.1). 
• Because contraception is required throughout the study for both males and females, the use of 
an acceptable method throughout the study will be discussed with all subjects (Section 7.8). 
• Collect a urine sample for pregnancy testing for women of childbearing potential (Section 7.8). 
• Administer the Columbia–Suicide Severity Rating Scale (C-SSRS) (Section 9.6.3). 
• Perform the TNmAS-MAL assessment (Section 8.2). 
• Administer the EDSS assessment (Section 8.3). 
• Administer the PGIC questionnaire (Section 8.1).   
• Administer the USP questionnaire (Section 9.6.2). 


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• Dispense the study medication.  The investigator will explain to the subject how to take the 
study medication and the regimen to be followed until the next visit (Section 7.5). 
• The site will administer the first daily dose of study medication to the subject. 
• Record any adverse events (AEs) that have occurred (Section 9.7). 
• Record all concomitant medications/therapies the subject is currently taking (Section 7.7). 
• Schedule the next study visit. 
 
6.3 
Visits 1, 2, 3, 5, and 6 – Weeks 2, 6, 14, 42, and 54 
Assessments/procedures will include the following: 
• Record vital sign measurements, including BP, heart rate, respiratory rate, and body 
temperature (Section 9.2). 
• At Visits 2, 3, 5, and 6, collect blood and urine samples for hematology, serum chemistry, and 
urinalysis (Section 9.5).  Subject should be fasting if possible. 
• Collect a urine sample for pregnancy testing for women of childbearing potential (Section 7.8). 
• Administer the C-SSRS (Section 9.6.3). 
• Administer the USP questionnaire (Section 9.6.2). 
• Dispense the study medication.  The investigator will explain to the subject how to take the 
study medication and the regimen to be followed until the next visit (Section 7.5). 
• Collect unused study medication, assess compliance, and study drug accountability 
(Section 7.9). 
• Record any AEs that have occurred (Section 9.7). 
• Record all concomitant medications/therapies the subject is currently taking (Section 7.7). 
• Schedule the next study visit. 
6.4 
Visit 4 – Week 28 
Assessments/procedures will include the following: 
• Record weight (Section 9.4). 


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• Record vital sign measurements, including BP, heart rate, respiratory rate, and body 
temperature (Section 9.2). 
• Collect blood and urine samples for hematology, serum chemistry, and urinalysis (Section 9.5).  
Subject should be fasting if possible. 
• Perform a standard 12-lead ECG (Section 9.6.1). 
• Collect a urine sample for pregnancy testing for women of childbearing potential (Section 7.8). 
• Administer the C-SSRS (Section 9.6.3). 
• Perform the TNmAS-MAL assessment (Section 8.2). 
• Administer the EDSS assessment (Section 8.3). 
• Administer the USP questionnaire (Section 9.6.2). 
• Dispense the study medication.  The investigator will explain to the subject how to take the 
study medication and the regimen to be followed until the next visit (Section 7.5). 
• Collect unused study medication, assess compliance, and study drug accountability 
(Section 7.9). 
• Record any AEs that have occurred (Section 9.7). 
• Record all concomitant medications/therapies the subject is currently taking (Section 7.7). 
• Schedule the next study visit. 
6.5 
Visit 7 End of Taper (Telephone Visit) – Week 56 
• Record any AEs that have occurred (Section 9.7). 
• Record all concomitant medications/therapies the subject is currently taking (Section 7.7). 
• Schedule the final study visit. 
6.6 
Visit 8 (Final Visit or Early Termination) – Week 60  
The assessments/procedures listed for Visit 8 (Final Visit) are to be completed by all subjects 
regardless of whether they complete the entire study or prematurely withdraw from the study.  If 
the Final Visit is performed before Week 60 due to early termination of the subject, every effort 
should be made to perform the clinical evaluations as follows, especially blood sampling for 
hematology and serum chemistry, urinalysis, ECG, and the 2-week study drug taper.  
Assessments/procedures will include the following: 
• Record weight (Section 9.4). 


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• Record vital sign measurements, including BP, heart rate, respiratory rate, and body 
temperature (Section 9.2). 
• Collect blood and urine samples for hematology, serum chemistry, and urinalysis (Section 9.5).  
Subject should be fasting if possible. 
• Perform a standard 12-lead ECG (Section 9.6.1). 
• Collect a urine sample for pregnancy testing for women of childbearing potential (Section 7.8). 
• Administer the C-SSRS (Section 9.6.3). 
• Perform the TNmAS-MAL assessment (Section 8.2). 
• Administer the EDSS assessment (Section 8.3). 
• Administer the PGIC questionnaire (Section 8.1). 
• Administer the USP questionnaire (Section 9.6.2). 
• Collect unused study medication, assess compliance, and study drug accountability 
(Section 7.9). 
• Record any AEs that have occurred (Section 9.7). 
• Record all concomitant medications/therapies the subject is currently taking (Section 7.7). 
7 
STUDY TREATMENTS 
7.1 
Treatments Administered 
All subjects will begin treatment with AERT at 40 mg per day (2 x 20 mg) for 3 days, then increase 
to 60 mg per day (3 x 20 mg) for 3 days, and then increase to 80 mg per day (4 x 20 mg).  Once 
the subject has reached the maintenance dose, they will remain on that dose for approximately 
1 year (Figure 2).  The maintenance dose will be the highest tolerated dose, not exceeding 80 mg 
per day.  The description of study drug kits and treatments is shown below in Table 2.  Subjects 
may choose to taper study drug after Visit 3 if they experience adverse events.  Direct consultation 
with the investigator site must be conducted before consideration for dose taper.  Dose tapers 
should occur over the course of 9 days in 20 mg increments.  Subjects should be encouraged to 
titrate back to 80 mg once adverse events subside or remain on the maximally tolerated AERT 
dose.  Up to 3 dose tapers over the course of the clinical study are permitted.   
 


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Table 2: 
Study Drug Kits and Treatments, Study OS440-3005 
Dosage form 
description: 
Blue, round biconvex tablets. 
Package 
description: 
HDPE white bottles with 60 active 20-mg tablets. 
Daily dose: 
40, 60, and 80 mg arbaclofen depending on the study day.  There will be a 9-day titration 
period (3 days at 40 mg/day, 3 days at 60 mg/day, and then increase to 80 mg/day), then an 
approximately 1-year maintenance period at 80 mg/day or the highest tolerated dose, 
followed by a 2-week taper period.  Study tablets will be taken twice daily (BID). 
Cumulative 
maximal dosage: 
up to 28,420 mg arbaclofen 
Manufacturer: 
Osmotica Pharmaceutical US LLC, Marietta, GA 30062 
7.1.1 
Treatment Administration 
The study medications will be administered orally twice daily (every 12 hours, or BID) without 
regard to food.  Note:  For the 60 mg/day titration, this means 1 x 20 mg AERT in the morning 
and 2 x 20 mg AERT in the evening. 
Once the subject has reached the maintenance dose, they will remain on that dose for 
approximately 1 year.  The maintenance dose will be the highest tolerated dose, not exceeding 
80 mg per day.  All attempts should be made for subjects to titrate to the 80 mg per day dose.  If 
subjects experience untoward tolerability issues due to AERT, they may taper study drug only 
under the guidance of the study site (i.e., in 20 mg increments per week).  Subjects may 
subsequently attempt study drug taper if the investigator deems this clinically appropriate.  There 
will be no taper phase for subjects who solely achieve a 40 mg per day maintenance dose.  Subjects 
may attempt to titrate to the target dose of 80 mg per day, if tolerability issues have resolved. 
If a subject misses 7 or more consecutive days of dosing AND has taken less than 80% of their 
doses of study medication in a 42-day (6-week) period, then the subject must be discontinued (see 
Section 12.4). 
7.1.2 
Labeling of Study Drug 
Study medication will be provided in labeled bottles.  The labels will include all information 
required by federal and local regulations. 
7.1.3 
Storage of Study Drug 
Arbaclofen extended-release tablets must be stored at 20°C to 25°C (68°F to 77°F), excursions 
permitted to between 15°C and 30°C (59°F to 86°F) (see USP Controlled Room Temperature.  At 
study sites, all study medication must be stored, secured, and locked in a safe place. 


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7.2 
Study Drug Accountability 
The Principal Investigator will have overall responsibility for the use of the study drug.  The 
Principal Investigator or designee will confirm receipt of the study drug by signature and date.  A 
copy of this receipt must be returned to the Sponsor or designee when the contents of the drug 
shipment have been verified.  In addition, an accurate study drug dispensing record that specifies 
the date and amount dispensed to each subject must be kept in accordance with the study drug 
accountability form.  This inventory record must be available for inspection during an audit (e.g., 
by Sponsor or a regulatory agency).  At the conclusion of the study, the Principal Investigator must 
provide a copy of this record to the Sponsor. 
Under no circumstances will the investigator allow the investigational drugs to be used other than 
as directed by this protocol.  The study medication must be protected from unauthorized access 
(e.g., in a locked storage facility).  Qualified study personnel must use the specified randomization 
system to assign subjects to treatment.  Reasons for digression from the expected dispensing 
regimen must also be recorded. 
At the end of the study, all medication must be reconciled.  Any unused medication will be 
inventoried by the investigator or designee and retained by the site until instructed otherwise by 
Sponsor. 
7.3 
Handling and Disposal of Study Drug 
The study drug must be protected from unauthorized access (e.g., in a locked storage facility). 
Any unused, partially used, or empty bottles of study drug will be returned to the Sponsor or 
designee by the time of the site’s close-out visit.  Receipt, distribution, and return of the study drug 
must be properly documented on forms provided by the Sponsor or designee. 
7.4 
Method of Assignment of Study Drug 
This is an open-label study and all subjects will begin treatment with AERT at 40 mg per day 
(20 mg BID) for 3 days, then increase to 60 mg per day (20 mg in the morning and 2 x 20 mg in 
the evening) for 3 days, and then increase to 80 mg per day (2 x 20 mg BID).  Once the subject 
has reached the maintenance dose, they will remain on that dose for approximately 1 year.  The 
maintenance dose will be the highest tolerated dose, not exceeding 80 mg per day.  Subject will be 
allowed to taper the 80-mg/day dose for issues of tolerability on at most three occasions.  If 
tolerability issues persist, the subject will be required to discontinue from the study. 
After Baseline procedures have been completed, authorized site personnel will acknowledge that 
the applicable subject met all the specified inclusion criteria (Section 5.1) and none of the exclusion 
criteria (Section 5.2) and an enrollment number will be sequentially assigned. 


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7.5 
Selection and Timing of Doses in the Study 
There will be a 9-day titration period (3 days at 40 mg/day, 3 days at 60 mg/day, and 3 days at 
80 mg/day), then a 1-year maintenance period, followed by a 2-week taper period.  The 
maintenance dose will be the highest tolerated dose, not exceeding 80 mg per day.  Subjects who 
discontinue early should also follow the 2-week taper period.  Figure 2 presents the dosing regimen 
flowchart, including titration and taper, to be used during the study. 




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7.6 
Emergency Unblinding 
This is an open-label study. 
7.7 
Prior and Concomitant Therapy 
The inclusion and exclusion criteria (Section 5.1 and 5.2, respectively) provide details on 
prohibited medications and food and the permitted duration since their last use prior to Baseline 
and/or study drug administration.  For de novo subjects, all medications taken within 30 days 
before Baseline are to be recorded in the electronic case report form (eCRF).  Eligible de novo 
subjects will undergo an up to 21-day washout period (no drug onboard) for withdrawal of all 
medications used for anti-spasticity and/or muscle relaxation prior to Baseline (see Inclusion 
Criterion 6).  Any subject will be ineligible for the current open-label study if they are 
concomitantly using any of the medications listed in Appendix 5 (see Exclusion Criterion 5).   
Table 3 presents the half-life, taper period, and washout period for specific anti-spasticity and/or 
muscle relaxation medications.  Tapering of an existing anti-spasticity drug depends on the dose 
of the drug and other conditions.  The investigator should use medical judgment to safely taper the 
dose.  Under most conditions, the taper should take no more than 2 weeks.  For anti-spasticity 
medications not shown in Table 3, please contact the medical monitor for discussions of the 
washout period. 
 
Table 3: 
Taper and Washout Periods for Specific Anti-spasticity and/or 
Muscle Relaxation Medications, Study OS440-3005 
Drug 
Half-Life 
(hours) 
Taper Period 
Washout Period 
Baclofen 
3 to 5 
3 to 14 days 
1 day 
Clonidine 
12 to 16 
3 to 14 days 
3 days 
Dantrolene 
8 to 9 
3 to 14 days 
2 days 
Gabapentin 
5 to 7 
3 to 14 days 
2 days 
Zanaflex 
3 
3 to 14 days 
1 day 
Diazepam 
100 
3 to 14 days 
3 weeks 
 
Other than anti-spasticity medications, all conventional medications regularly used for the 
treatment of MS and all non-pharmacological therapies (intended to alleviate spasticity, e.g., 
physiotherapy) are allowed provided they have been taken/administered for at least 1 month prior 
to enrollment and no dose adjustments are expected for the duration of this study. 
Changes in either the dose or frequency of concomitant medications taken for the treatment of MS 
should not be made for the duration of this study.  In the event a dose adjustment is needed for a 
concomitant medication, the investigator will contact the Sponsor to determine if the subject may 
remain in the study or needs to be withdrawn. 


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If a subject is receiving disease-modifying medications (especially interferons, see Inclusion 
Criterion 5), study visits should be scheduled prior to administration and, if possible, at a consistent 
time point during the study from when these drugs are administered in order to avoid interference 
with the temporary increase in spasticity that these medications may produce. 
Subjects who experience an acute MS exacerbation/relapse (symptoms including but not limited 
to visual disturbance, dizziness, tingling, or extreme fatigue lasting greater than 24 hours and 
occurring at least 30 days after a previous relapse) requiring immediate therapy or adjustment in 
disease-modifying medication dose (e.g., oral or intravenous high-dose steroid therapy) will be 
discontinued from this study.   
Other medication that is considered necessary for the subject’s safety and well-being may be given 
at the discretion of the investigator.  The administration of all medication (including investigational 
products) will be recorded in the appropriate sections of the eCRF. 
Data collection for concomitant medications will include information on indication, dose, route, 
dosing frequency, start date, stop date, and will continue throughout the study. 
The investigator or study staff will ask the subject at every study visit whether they have taken any 
new medications or had changes in their current medications since the last study visit.  It is the 
responsibility of the investigator to ensure that any change in concomitant medications during the 
study is recorded in the source documentation and entered in the eCRF. 
7.8 
Use of Contraception and Pregnancy Testing 
Prior to study enrollment, females of childbearing potential and female partners of male subjects 
must be advised of the importance of avoiding pregnancy during study participation and the 
potential risk factors for an unintentional pregnancy.  Females of childbearing potential include 
any female who has experienced menarche and who has not undergone successful surgical 
sterilization (hysterectomy, bilateral tubal ligation/occlusion, or bilateral oophorectomy) or is not 
postmenopausal (defined as amenorrhea >12 consecutive months).  De novo premenopausal 
women of childbearing potential must have a negative serum pregnancy test within 21 days before 
Baseline and all enrolled subjects, if they are sexually active or become sexually active during the 
study, must use an effective method of birth control such as those listed below during the course 
of the study.  Urine pregnancy testing will be done at Visits 1 through 8. 
The following is not an all-inclusive list; the subject must discuss with the investigator the most 
appropriate form of birth control: 
• Hormonal methods 
o Oral contraceptives 
o Implant 
o Injection 
o Transdermal patch 


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o Intravaginal ring 
• Intrauterine device (hormonal or non-hormonal) 
• Barrier methods 
o Condom (male or female) with spermicide 
o Diaphragm with spermicide 
• Complete abstinence 
7.9 
Treatment Compliance 
Subject compliance will be based on drug accountability information.  Non-compliance will be 
defined as subjects taking less than 80% or more than 120% of prescribed study medication overall 
as assessed by the amount of study drug returned by the subject at the end of the study.  If a subject 
misses 7 or more consecutive days of dosing AND has taken less than 80% of their doses of study 
medication in a 42-day (6-week) period, then the subject must be discontinued. 
8 
EFFICACY ASSESSMENTS 
8.1 
Patient Global Impression of Change 
The PGIC is a standard instrument that is a well validated outcome measure.  The 7-point PGIC 
measures change in the subject’s overall status using the following categorical scale: 
• 1 = Very much improved 
• 2 = Much improved 
• 3 = Improved 
• 4 = No change 
• 5 = Minimally worse 
• 6 = Much worse 
• 7 = Very much worse 
The PGIC will be completed at the visits specified in Table 1.  The PGIC is provided in Appendix 3.  
8.2 
Total Numeric-Transformed Modified Ashworth Scale 
The TNmAS is considered the primary clinical measure of muscle spasticity in subjects with 
neurological conditions.  It is a useful 6-point rating scale to measure abnormality in tone or the 
resistance to passive movements, since there is no clinically direct method for measuring spasticity. 


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When initially developed in the early 1960s (Ashworth 1964) to estimate the efficacy of 
anti-spastic drugs in subjects with MS, it was a 5-point scale, with a grade score of 0 to 4.  In 1987, 
the grade “1+” was added and slight changes were proposed on the definitions of each score in 
order to increase the sensitivity of the measure and facilitate scoring.  The new measure was then 
called the Modified Ashworth Scale (mAS) and it is considered the gold standard for measuring 
spasticity (Bohannon and Smith 1987). 
Although there are no standardized guidelines for its use, it can be applied to muscles of both the 
upper or lower body.  The rater should extend the client’s limb from a position of maximal flexion 
to maximal extension until the first soft resistance is felt.  Moving a subject’s limb through its full 
range of motion should be done within 1 second by counting “one thousand and one.” 
It is suggested that the testing of the upper limbs should take place while the subject is lying supine, 
with the upper limbs parallel to the trunk, elbows extended, wrists in a neutral position, and the 
lower limbs positioned parallel to one another.  Exceptions are made for the shoulder extensors, 
where the arm should be moved from extension to 90 degrees of flexion, and for the shoulder 
internal rotators, where the arm should be moved from neutral to a maximum external rotation.  
For the lower limbs, it is recommended that the subject be lying on their side.  Specifically for 
testing the soleus muscle, the hips and knees should be positioned in 45 degrees of flexion and the 
ankle is moved from maximum plantar flexion to maximum dorsiflexion.  For the gastrocnemius 
muscle, hips should be in 45 degrees of flexion with the knees in maximum extension and the 
ankle is moved from maximum plantar flexion to maximum dorsiflexion.  For the quadriceps 
femoris muscle, knees and hips should be in maximal extension and the knee is moved from 
maximum extension to maximum flexion.  Throughout testing, the subject should be instructed to 
remain calm and relaxed, and when repeated testing is undertaken, testing should be initiated at 
the same time of the day to minimize possible changes in spasticity levels due to medication 
interaction. 
To arrive at the TNmAS-MAL score, the total numerical score of the most affected limb accounts 
for the sum of the 3 main joint muscular group scores. 
The TNmAS-MAL assessment will be performed by the investigator who has been appropriately 
trained to perform and assess the TNmAS-MAL, and when possible, all TNmAS-MAL 
assessments should be performed for a particular subject by the same person throughout the study 
and always prior to any scheduled lab draw.  The most affected limb will be determined by the 
investigator. 
The TNmAS-MAL assessment will be done at the visits specified in Table 1.  The mAS and 
TNmAS-MAL are provided in Appendix 1. 
8.3 
Expanded Disability Status Scale 
The EDSS is a method of quantifying disability in MS and monitoring changes in the level of 
disability over time.  It is widely used in clinical trials and in the assessment of people with MS.  
The scale was developed by John Kurtzke in 1983 as an advance from his previous 10-step 
Disability Status Scale (DSS) (Kurtzke 1983).  The EDSS scale ranges from 0 to 10 in 0.5-unit 
increments that represent higher levels of disability. 


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EDSS steps 1.0 to 4.5 refer to people with MS who are able to walk without any aid and is based 
on measures of impairment in eight functional systems (FS):  pyramidal (weakness or difficulty 
moving limbs), cerebellar (ataxia, loss of coordination, or tremor), brainstem (problems with 
speech, swallowing, and nystagmus), sensory (numbness or loss of sensations), bowel and bladder 
function, visual function, cerebral (or mental) functions, and other.  Each FS is scored on a scale 
of 0 (no disability) to 5 or 6 (more severe disability).  EDSS steps 5.0 to 9.5 are defined by the 
impairment to walking. 
The EDSS assessment will be done at the visits specified in Table 1.  The EDSS is provided in 
Appendix 2. 
9 
SAFETY ASSESSMENTS 
Safety will be assessed by the monitoring of AEs volunteered, observed, and elicited by general 
questioning in a non-suggestive manner.  Changes in vital signs, clinical laboratory test results, 
12-lead ECGs, the USP questionnaire, and the C-SSRS will also be assessed. 
9.1 
Medical/Surgical History 
A complete medical and surgical history will be obtained at Baseline (Screening for de novo 
subjects), which will record previous respiratory, cardiovascular, gastrointestinal, hepatic, 
nephron-urologic, metabolic, allergic, infectious, gynecologic, musculoskeletal, endocrine, 
neurologic, psychiatric, dermatologic, allergic, hematologic, and any other diseases. 
9.2 
Vital Signs 
Vital signs will be measured at all visits.  Blood pressure measurements will be made using a 
sphygmomanometer with an appropriate cuff size for the individual subject. 
To evaluate the potential of arbaclofen to trigger orthostatic hypotension, BP and heart rate will 
be measured twice at each study visit.  Orthostatic testing should take place in a quiet room, 
preferably at a temperature between 20°C and 24°C (68°F to 75°F).  Emptying the bladder before 
testing is also recommended.  The diagnosis of orthostatic hypotension is established by measuring 
the BP in the supine and then in the standing position, at least 3 minutes apart, and noting a 
substantial drop accompanied by symptoms of dizziness or syncope.  A positive response is 
considered if systolic BP falls below 20 mmHg and diastolic BP 10 mmHg of baseline.  If 
symptoms occur, the subject should be returned to the supine position immediately. 
Vital signs, including BP, heart rate, respiratory rate, and body temperature, will be measured after 
the subject has been in a supine position quietly for 10 minutes.  Then, with the subject in a 
standing position, BP and heart rate will be measured again after the supine assessment is 
completed. 
9.3 
Physical Examination 
A physical examination will be performed at Baseline (Screening for de novo subjects) and will 
include the following categories:  general, head, ears, eyes, nose and throat, neck, 


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heart/cardiovascular, 
lungs/respiratory, 
abdomen, 
breast 
(performed 
by 
palpation), 
musculoskeletal (back and extremities), neurological, lymph nodes, and skin. 
9.4 
Weight and Height 
Weight will be measured at Baseline (Screening for de novo subjects), at Visit 4 (Week 28), and 
at Visit 8 (Final Visit or Early Termination).  Height will be measured only at Baseline.  At each 
site the same balance will be used for all measurements.  Subjects will wear only indoor clothing 
without shoes. 
9.5 
Clinical Laboratory Tests 
A central laboratory will be used for this study.  Blood draws for chemistry and hematology tests 
and urine samples for urinalyses will be collected and sent to the central laboratory.  Table 4 
presents the specific clinical laboratory tests to be evaluated. 
All laboratory values that are outside of the normal range for that parameter will be so flagged 
when reported to the site.  The investigator will annotate laboratory reports to indicate whether 
any abnormal laboratory value is considered clinically significant.  Any abnormal laboratory value 
that is considered clinically relevant should be confirmed by a repeated laboratory test when 
possible. If a clinically significant laboratory abnormality requires treatment or is the reason for a 
subject being discontinued from the study, the abnormal result must be classified as an AE.  If 
clinically relevant and considered an AE, the event must be followed until resolution or as long as 
medically necessary and be recorded on the AE page of the eCRF. 
Table 4: 
Clinical Laboratory Tests, Study OS440-3005 
Hematology 
Urinalysis 
Serum Chemistry 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) 
count with differential 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocytes esterase 
Specific gravity 
Color 
 pH 
Protein 
Microscopic examination of urine: 
• 
Epithelial cells 
• 
Casts (RBC, WBC, etc.) 
• 
Red blood cells 
• 
White blood cells 
Urine pregnancy test (at the site) 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase 
Aspartic acid transaminase (AST) 
Bicarbonate 
Blood urea nitrogen (BUN) 
Chloride 
Creatinine 
Creatinine kinase 
Glucose 
Potassium 
Sodium 
Total bilirubin (if elevated, obtain 
direct bilirubin) 
Uric acid 
ALT = alanine transaminase; AST = aspartate transaminase; BUN = blood urea nitrogen; RBC = red blood cell; 
WBC = white blood cell 


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Samples for clinical hematology, serum chemistry, and urinalysis will be obtained for each subject 
and sent to a central laboratory at the visits specified in Table 1.  Site personnel will do a routine 
urinalysis by dipstick on site and the central laboratory will do a complete microscopic urine 
examination.  Site personnel will also complete a urine pregnancy test for female subjects of 
childbearing potential on site at the visits specified in Table 1 (see Section 7.8 regarding serum 
pregnancy testing in premenopausal women of childbearing potential at Baseline [Screening for 
de novo subjects]). 
Sample collection kits, requisition slips, and shipping boxes will be supplied by the central 
laboratory.  Sample collection procedures and shipping instructions will be detailed in the 
laboratory manual.  Study centers must be equipped to store the samples according to the 
laboratory manual procedures before shipping samples to the central laboratory. 
9.6 
Other Safety Assessments 
9.6.1 
Electrocardiograms 
A standard 12-lead ECG will be performed on subjects in the supine position.  Subjects will have 
rested in the supine position for at least 5 minutes prior to the ECG.  The time at which the subject 
assumed the supine position will be recorded to confirm the rest time.  ECGs will be done at the 
visits specified in Table 1. 
9.6.2 
Urinary Symptom Profile© Questionnaire 
The USP is a health-related quality of life questionnaire developed in 2005 by the French 
Association of Urology and validated in 2008 (Haab et al 2008).  It is composed of 13 items in 
3 dimensions to assess urinary symptoms among adults (both men and women) with stress, urge, 
overactive bladder, or urinary obstructive symptoms.  It is administered with a time frame over the 
past 4 weeks.  The USP is a valuable tool for self-administration by the subject to complement 
clinical measures and diagnosis due to it being a valid and reliable questionnaire providing 
comprehensive evaluation of all urinary disorders and their severity.  It also allows the pathology 
screening and contributes to the differential diagnosis of these symptoms.  Due to the potential risk 
of arbaclofen to produce urinary problems, mainly at the bladder level (as seen in some animal 
toxicological studies; see the current arbaclofen Investigator’s Brochure [IB]), the utilization of 
this questionnaire has been implemented in the context of this study to monitor urinary 
symptomatology and rule out any complication that could be developed during the course of the 
study.  An increase of 4 points in the total USP score from the previous visit will be considered an 
AE. 
The USP questionnaire will be completed by the subject at the visits specified in Table 1.  The 
USP is provided in Appendix 6. 
9.6.3 
Columbia–Suicide Severity Rating Scale 
The C-SSRS will be administered by the investigator or a qualified designee trained in its 
administration.  The C-SSRS is a standardized instrument that was developed to assess the severity 
of and monitor changes in suicidal ideation and behavior.  Four constructs are measured.  The first 
is severity of ideation rated on a 5-point ordinal scale.  The second is intensity of ideation, which 


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comprises 5 items (frequency, duration, controllability, deterrents, and reason for ideation) each 
rated on a 5-point ordinal scale.  The third is behavior rated on a nominal scale that includes actual, 
aborted, and interrupted attempts; preparatory behavior; and non-suicidal self-injurious behavior.  
The fourth is lethality, which assesses actual attempts; actual lethality is rated on a 6-point ordinal 
scale, and if actual lethality is zero, potential lethality of attempts is rated on a 3-point ordinal scale. 
The C-SSRS assessment will be done at the visits specified in Table 1.  The C-SSRS is provided 
in Appendix 4. 
9.7 
Adverse Events 
9.7.1 
Method of Determining Adverse Events 
Safety assessments will include recording AEs reported spontaneously by the subject or observed 
by the investigator.  AEs will be recorded at each visit throughout the study.  All AEs will be 
recorded on the AE log of the eCRF.  Every attempt should be made to describe the AE in terms 
of a diagnosis.  If a clear diagnosis has been made, individual signs and symptoms will not be 
recorded unless they represent atypical or extreme manifestations of the diagnosis, in which case 
they should be reported as separate events.  If a clear diagnosis cannot be established, each sign 
and symptom must be recorded individually. 
Subjects should be asked whether, since the time of the last observation or visit, they had any of 
the following: 
• Experienced any changes in well-being. 
• Used any new medications. 
• Changed medication regimens (both prescription and over-the-counter). 
• Were admitted to a hospital or had any accidents. 
All questions should be of a general nature and should not suggest symptoms. 
When an AE is suspected, all relevant evaluations will be performed and appropriate treatment 
provided.  Additional follow-up will be done as necessary (Section 9.7.4) and recorded in the 
subject’s source documents, and the results will be provided to the Sponsor. 
9.7.2 
Adverse Event Definitions 
9.7.2.1 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease that appears or worsens in a 
subject after the subject signs the ICF for a clinical study. 
Examples of what may be considered an AE include any of the following: 
• A new illness. 


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• An exacerbation of a sign or symptom of an underlying condition or of a concomitant illness 
unrelated to participation in the clinical study or an effect of the study drug or comparator drug. 
No causal relationship with the study drug is implied by the use of the term “adverse event.”  An 
exacerbation of a pre-existing condition/illness is defined as a more frequent occurrence or as an 
increase in the severity of the pre-existing condition/illness during the study.  Planned or elective 
surgical procedures for pre-existing conditions that have not worsened are not AEs.  However, any 
complication that occurs during a planned or elective surgery is an AE.  (If the event meets the 
criteria for a SAE, such as an extended hospitalization, it will be considered an SAE).  Conditions 
leading to unplanned surgical procedures may also be AEs. 
9.7.2.2 
Serious Adverse Events 
An SAE is any AE that: 
• Results in death. 
• Is life-threatening. 
Note:  The term “life-threatening” refers to any AE that, as it occurs, puts the subject at 
immediate risk of death.  It does not refer to an AE that hypothetically might have caused death 
if it were more severe. 
• Results in hospitalization or prolongation of current hospitalization (not including 
hospitalization for a pre-existing condition that has not increased in severity or frequency from 
the subject’s underlying medical condition prior to entry into the study). 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect in the offspring of a subject 
• Is another serious event (important medical events) 
Note:  Important medical events may not be immediately life-threatening or result in death or 
hospitalization but may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject or require medical or surgical intervention to prevent one of 
the outcomes listed above.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization; or development of drug dependency 
or drug abuse. 
9.7.2.3 
Severity of Adverse Events 
“Severity” of the AE refers to the extent to which an AE affects the subject’s daily activities and 
differs from “Serious”, which is a regulatory classification.  Severity will be categorized according 
to the following criteria: 


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• Mild:  The symptom has a negligible effect or no impairing effect on the subject’s normal 
function. 
• Moderate:  The symptom impairs the subject’s normal function to some extent. 
• Severe:  The symptom has an obvious, significantly impairing effect on the subject’s normal 
function. 
9.7.2.4 
Relationship of Adverse Events to Study Treatments 
“Causality” refers to the relationship of the AE to study drug and will be categorized according to 
the following criteria: 
• Unlikely:  There is no medical evidence to suggest that the AE may be related to study drug 
usage, or there is another more probable medical explanation. 
• Possible:  There is medical evidence to suggest that there is a reasonable possibility that the 
AE may be related to study drug usage.  However, other medical explanations cannot be 
excluded as a possible cause. 
• Probable:  There is strong medical evidence to suggest that the AE is related to study drug 
usage. 
9.7.2.5 
Adverse Events Expectedness 
Expected AEs are defined as those described in the arbaclofen IB.  If an event increases in intensity 
or severity from that described in the IB, it will be considered unexpected. 
9.7.3 
Reporting Adverse Events 
Adverse events that occur from the time of informed consent through completion of the last study 
visit should be reported.  Any AE that the investigator becomes aware of that occurs within 30 days 
of study completion or withdrawal should also be reported. 
Any SAEs occurring in a subject receiving study medication must be reported to the Sponsor 
within 24 hours of the site being informed of the event, even if the event does not appear to be 
drug-related.  This reporting must be done by faxing the appropriate completed form (SAE form 
or Exposure during Pregnancy form) to the Sponsor.  Any pertinent follow-up information should 
be provided in a similar manner.  Contact information is provided below: 




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collected on the appropriate form.  If pregnancy is confirmed, the subject must be withdrawn from 
the study and the Sponsor and site monitor notified.  Additional relevant information about the 
confirmed pregnancy will be recorded on the appropriate form(s); pregnancy will not be captured 
as an AE. 
The subject should be followed until the outcome of the pregnancy is known. 
9.8 
Appropriateness of Safety Measurement 
The safety assessments to be utilized in this study are standard safety measures in clinical trials. 
10 DATA SAFETY MONITORING BOARD 
A Data Safety Monitoring Board (DSMB) will oversee study subject safety with respect to AEs 
and clinically important lab values.  The committee will include three individuals with collective 
experience and knowledge about clinical trial conduct, study subject safety, MS, and bladder 
dysfunction, a condition common in MS subjects.  DSMB members will be independent of the 
Sponsor, study sites, and the managing vendors, and will have no other role in the trial.  The DSMB 
will convene after 33%, 66%, and 100% of the trial is enrolled.  The role of the DSMB will be 
governed by a DSMB charter. 
11 STATISTICAL DESIGN AND ANALYSIS 
11.1 
Statistical Analysis Plans 
A detailed Statistical Analysis Plan (SAP) will be finalized prior to study termination. 
Descriptive statistics (n, mean, median, standard deviation [SD], minimum, and maximum for 
continuous data; frequencies and percentages for categorical data) will be used to summarize study 
data.  Unless specified otherwise, all statistical testing will be two-sided and performed using a 
significance level of 0.05. 
11.2 
Analysis Populations 
The following population will be defined for analysis: 
• Safety population:  Includes all subjects who receive at least one dose of open-label study 
treatment and have at least one post-dose visit.  Subjects will be analyzed according to the 
treatment received.  This population will be used for all safety and efficacy analyses. 
11.3 
Determination of Sample Size 
In total, approximately 300 subjects are to be enrolled in this study (i.e., both rollover and de novo 
subjects).  It is anticipated that approximately 50% of subjects randomized into the double-blind 
study (Study OS440-3004) may roll over into this open-label study, and US subjects who did not 
participate in the previous double-blind Study OS440-3004 (i.e., de novo subjects) may also enroll 
into the current study.  The number of subjects at each site will be determined primarily by the rate 
of recruitment in Study OS440-3004.  No statistical rationale for subject number is provided.   


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The sponsor has previously completed a 1-year, open-label safety study (Study OS440-3003) at 
the 40-mg per day dose. In Study OS440-3003 a total of 148 subjects were treated. Study 
OS440-3005 is designed to enrich the existing safety database and provide long-term safety and 
tolerability data at the maximum daily dose of 80 mg/day.  Target recruitment includes at least 100 
subjects treated at 6 months and 50 subjects treated for 1 year at 80-mg per day. 
11.4 
Efficacy Analyses 
11.4.1 
Efficacy Endpoints 
11.4.1.1 
Patient Global Impression of Change 
Descriptive summaries for PGIC scores will be tabulated by study visit and for change from 
baseline. 
11.4.1.2 
Total Numeric-Transformed Modified Ashworth Scale 
Descriptive summaries for TNmAS-MAL scores will be tabulated by study visit and for change 
from baseline. 
11.4.1.3 
Expanded Disability Status Scale 
Descriptive summaries for EDSS scores will be tabulated by study visit and for change from 
baseline. 
11.5 
Safety Endpoints 
Safety endpoints will be reported on the Safety population.  Subjects will be reported according to 
the treatment they actually received.  Safety assessment will be based on descriptive statistics and 
individual subject listings.  No statistical tests will be performed for any of the safety assessments. 
All reported AEs will be mapped to the Medical Dictionary for Regulatory Activities (MedDRA) 
system organ classifications (SOCs) and preferred terms (PTs).  If a subject reports multiple events 
of a single PT, the greatest severity and strongest investigator assessment of relationship to study 
treatment will be assigned to that PT.  Should an event have a missing severity or relationship, it 
will be classified as having the highest severity and/or strongest relationship to study drug.  
Summaries of treatment-emergent AEs (TEAEs) will include any AEs reported beginning with the 
first dose of study treatment on Day 1.  The occurrence of TEAEs will be summarized by treatment 
group using SOCs, PTs, and severity.  Separate summaries of treatment-emergent SAEs, TEAEs 
considered related to study treatment, and events leading to the discontinuation of study drug will 
be generated. 
Descriptive summaries of vital signs, clinical laboratory results, USP results, and the C-SSRS 
results will be presented by study visit and treatment group.  The number and percentage of 
subjects with treatment-emergent clinical laboratory abnormalities will be summarized by 
treatment group.  Normal range clinical laboratory shifts from baseline to end of study will be 
summarized by treatment group. 


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Concomitant medications will be coded using the World Health Organization (WHO) dictionary.  
These data will be summarized by treatment group.  Previous and concomitant medications will 
be presented in a data listing. 
Subject disposition will be presented for all subjects.  The numbers of subjects who complete the 
study and who discontinue early from the study will be provided.  The reasons for early 
discontinuation will also be presented. 
11.6 
Interim Analysis 
No interim analysis is planned. 
12 STUDY MANAGEMENT 
12.1 
Monitoring 
The investigator will be responsible for preparing and maintaining adequate and accurate source 
documents (medical records, ECGs, raw data collection forms, etc.) designed to record all 
observations and other pertinent data for each subject treated with the study drug.  The investigator 
will allow representatives of the Sponsor, contract designees, authorized regulatory authority 
inspectors, and the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) to have 
direct access to all documents pertaining to the study.  The investigator is to immediately notify 
the Sponsor of any regulatory authority inspections.  The investigator will be informed about the 
outcome of any Sponsor audit. 
This study will be monitored regularly, by or under supervision of a monitor from the Sponsor.  
The frequency of monitoring visits will be agreed upon by the Sponsor’s representative and the 
study site. 
Monitoring visits will take place on a regular basis according to the enrollment rate and number 
of subjects enrolled at each investigational site.  During these visits, the monitor will check the 
completion of the eCRF entries, compliance with the study protocol and with Good Clinical 
Practice - International Conference on Harmonization (GCP-ICH), and their agreement with the 
source data.  The monitor will also verify the correct use of the study drug.  At a final visit, the 
monitor will check all remaining material including the remaining quantities of the study drug and 
will organize their return to the Sponsor or designee.  At each visit, the investigator and staff will 
be expected to cooperate with the Sponsor’s representative(s) for the purposes of review and 
verification of protocol compliance, AE reporting, eCRFs, source documents, clinical supplies and 
inventory records, and any additional records as may have been previously arranged between the 
investigator and the Sponsor’s representative(s). 
The investigator and/or other designated study personnel are expected to contact the Sponsor with 
any study concerns and/or questions.  Contact information is provided in the Study Reference 
Manual for the site. 
12.2 
Protocol Amendments 
The Sponsor may propose to amend this protocol at any time. 


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No change to the protocol will be implemented until the Sponsor and the IRB/IEC have reviewed 
and approved the amendment. 
In the event of an emergency, the investigator shall implement any medical procedures deemed 
appropriate for subject safety.  All such procedures must have written documentation and be 
promptly reported to the Sponsor. 
12.3 
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the IRB/IEC approved protocol 
(intentional or unintentional).  Protocol deviations are to be reported to the IRB/IEC according to 
the IRB/IEC guidelines. 
12.4 
Withdrawal of Subjects 
Withdrawn subjects are those who do not complete all evaluations and procedures outlined in the 
protocol.  Subject withdrawal requires a 2-week dose taper.  A subject will be considered to have 
discontinued prematurely if he/she withdraws prior to completing Visit 8 (Final Visit).  If a subject 
misses 7 consecutive days AND has taken less than 80% of their doses of study medication in a 
42-day (6-week) period, then the subject must be discontinued.  Subjects may also be withdrawn 
from the study because of any of the following: 
• Adverse Event:  An AE that, in the opinion of the investigator or Sponsor, suggests that 
continued participation in the study is not in the subject’s best interest for safety reasons (also 
see Section 10).  All AEs that are present when the subject withdraws from the study will be 
followed as described in Section 9.7.4. 
• Medical Condition:  Any medical condition that, in the investigator’s judgment, would 
increase the risk or interfere with the evaluation of study objectives. 
• Lost to Follow-up:  Confirmed at minimum by two phone calls and a traceable letter without 
answer. 
• Subject Request:  Subject requests for any reason to be withdrawn or withdraws his/her 
consent.  Every effort should be made to determine the reason for the withdrawal request (e.g., 
AE, lack of efficacy, scheduling issues, etc.). 
• Protocol Deviation:  A subject may be withdrawn from the study at the discretion of the 
investigator or Sponsor due to poor compliance with protocol requirements that may 
compromise the study results or subject safety. 
• Enrollment in Another Study:  Enrollment in other protocols involving research drugs, 
medical devices, or surgeries. 
• Other Anti-spasticity Treatment:  Starting any other pharmacological anti-spasticity 
treatment during the study. 


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• Relapse: Subjects who experience an acute MS exacerbation/relapse (symptoms including but 
not limited to visual disturbance, dizziness, tingling, or extreme fatigue lasting greater than 
24 hours and occurring at least 30 days after a previous relapse) requiring immediate therapy 
or adjustment in disease-modifying medication dose (e.g., oral or intravenous high-dose steroid 
therapy). 
• Other:  Other reasons include but are not limited to:  Investigator decision that it is in the 
subject’s best interest to be withdrawn, administrative reasons, relocation of subject, etc.  If a 
subject or the partner of a subject becomes pregnant during the study, the subject will be 
withdrawn from the study and followed through conclusion of the pregnancy (see 
Section 9.7.5). 
When possible, a decision to discontinue a subject from the study should first be discussed with 
the Sponsor’s Medical Monitor.  If a subject is prematurely discontinued after randomization and 
prior to the final scheduled visit, every effort should be made to perform all of the Visit 8 
assessments (Table 1).  The reason(s) for early withdrawal must be recorded in the eCRF.  Subjects 
withdrawn from the study will not be replaced. 
12.5 
Termination of the Study 
The study may be terminated at any time at the request of the Sponsor or a regulatory authority, 
with proper and timely notification of all parties concerned.  The IRB/IEC will be informed 
promptly and the Sponsor or the investigator will supply reason(s) for the termination or 
suspension, as specified by the applicable regulatory requirements.  Otherwise, the study is 
considered terminated upon completion of all subject treatments and evaluations. 
12.6 
Publication Policy 
The data obtained in this study are the property of the Sponsor, who will make reasonable efforts 
to assure that the results are published in a peer-reviewed journal.  As some of the information 
concerning the investigational product and development activities at the Sponsor may be of a 
strictly confidential nature, any manuscript or other presentation of data must first be reviewed by 
the Sponsor before its submission. 
13 ETHICS 
13.1 
Conduct of the Study 
This study will be conducted in accordance with the ICH Harmonized Tripartite Guideline for 
GCP, 1997; the US Title 21 CFR parts 50, 56, and 312; and the ethical principles that have their 
origin in the Declaration of Helsinki.  The study will not begin until all of the requirements of the 
appropriate regulatory authorities have been fulfilled. 
13.2 
Institutional Review Boards and/or Independent Ethics Committees 
This protocol (and any changes), all consent forms, and subject consent procedures must be 
reviewed and approved by a properly constituted IRB/IEC.  The information presented to the 
IRB/IEC at the time initial approval is sought must include any plans for subject recruitment that 


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involve advertising or other direct contact with potential subjects outside of the doctor-subject 
relationship.  A letter of approval issued by the IRB/IEC must be sent to the Sponsor prior to 
initiation of the study.  Any changes made to the protocol must be approved by the IRB/IEC prior 
to implementation, except where needed to eliminate a potential imminent safety hazard to the 
subject.  In this case, immediate implementation may take place followed by IRB/IEC approval.  
Review and approval by the IRB/IEC for continuation of the study must take place at least once a 
year. 
13.3 
Written Informed Consent 
The investigator or designee will explain the nature of the study, its purpose and associated 
procedures, the expected duration, and the potential benefits and risks of participation to each 
subject prior to his/her entry into the study (i.e., before examinations and procedures associated 
with selection for the study are initiated).  Each subject will have ample opportunity to ask 
questions and will be informed about the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 
Following this informative discussion, the subject will be asked if he/she is willing to sign a 
statement of informed consent.  Only subjects who voluntarily sign the ICF may enter the study.  
The ICF must be reviewed and approved by the Sponsor and the IRB/IEC prior to its use. 
The original signed ICF will remain in the investigator’s files.  The investigator or designee will 
indicate in each subject’s source documents that he/she has informed the subject about the study 
and its procedures, the subject has signed and dated the ICF, and the subject has been given a copy 
of the signed ICF.  The investigator or designee will inform subjects of any new information that 
may be relevant to the subject’s willingness to continue in the study. 
13.4 
Subject Confidentiality 
The Sponsor ensures that the following have permission to review all study-related documents:  
monitor, auditor, IRB/IEC, and regulatory authorities.  The subject’s identity and study-related 
records will remain confidential throughout the duration of the study data collection and reporting 
process. 
A unique subject identification code will be assigned to each potential study subject.  The 
identification code protects the subject’s identity and is used in lieu of the subject’s name when 
reporting subject data.  The data will always maintain the confidentiality of the subject. 
The investigator or designee will review the subject data, which will be referenced using the 
subject identifier.  At the conclusion of the study, the data obtained may be presented to regional 
regulatory authorities but the subject’s identity will not be revealed.  In addition, if any clinical 
data obtained from the study are published in scientific journals or presented at scientific meetings, 
the subject’s identity will not be revealed. 
13.5 
Records Retention 
The investigator must maintain essential study documents (protocol and amendments, source 
documentation corresponding to all information contained in the eCRFs, signed ICFs, relevant 


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correspondence, and all other supporting documentation) until at least 2 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 2 years after the formal 
discontinuation of clinical development of the investigational product.  These documents should 
be retained for a longer period if required by the applicable regulatory requirements or the hospital, 
institution, or private practice in which the study is being conducted.  Subject identification codes 
(subject names and corresponding study numbers) will be retained for this same time period.  
Custody of the records may be transferred to another responsible party, acceptable to the Sponsor, 
who agrees to abide by the retention policies.  Written notice of transfer must be submitted to the 
Sponsor.  The investigator must contact the Sponsor prior to disposing of any study records. 
13.6 
Financing 
Funding for this study will be agreed between the investigator and the Sponsor and will be 
confirmed in writing before the study starts. 
Completion of Financial Disclosure Forms will be required before the study starts.  Any additions 
to the primary site personnel will necessitate the completion of new Financial Disclosure Forms.  
This information will also be collected at site closure and 1 year after the completion of the study. 
14 QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor and investigator will take all steps possible to ensure the accuracy, consistency, 
completeness, and reliability of the data, including participating in an investigator meeting and/or 
site initiation visit, routine site monitoring, review of eCRFs against source documents, and quality 
control checks. 
In addition, a representative from the Sponsor’s Clinical Quality Assurance Department may 
conduct periodic audits of the study processes, including, but not limited to, auditing the clinical 
site, laboratories, vendors and CROs, the clinical database, and the final study report. 
15 DATA HANDLING AND RECORD KEEPING 
This study will use web-based eCRFs developed through a validated, Electronic 
Records/Electronic Signatures-compliant platform (US Title 21 CFR Part 11).  The Sponsor’s 
Clinical Data Management department or designee will create the eCRFs and corresponding 
clinical database based on the final protocol. 
All site personnel who will be using this system will receive formal training on the system, after 
which each person will be issued a unique username and password.  Only the person who owns 
the username and password will enter the system using that username and password.  For data 
security reasons and to be in compliance with regulatory guidelines, usernames and passwords are 
not transferable. 
The investigator is responsible for all data entered via the remote data capture (RDC) system 
eCRFs and must confirm the accuracy of the data by electronically approving (signing) the eCRFs.  
This responsibility includes the timely completion and accuracy of the data entered into the eCRFs 
by their site personnel as well as the review and approval of some data entered directly into the 


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database (e.g., clinical laboratory results) by an external vendor.  The Sponsor will review the 
database to identify data errors or inconsistencies, which will be posted in the RDC system as 
queries for resolution.  In addition, the Sponsor may make obvious corrections to the data in the 
database (e.g., obvious errors in dates). 


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16 REFERENCE LIST 
Ashworth B. Preliminary Trial of Carisoprodol in Multiple Sclerosis. Practitioner. 
1964;192:540-542. 
Haab F, Richard F, Amarenco G, Coloby P, Arnould B, et al. Comprehensive evaluation of 
bladder and urethral dysfunction symptoms: development and psychometric validation of the 
Urinary Symptom Profile (USP) questionnaire. Urology. 2008;71(4):646-656. DOI: 
10.1016/j.urology.2007.11.100. Epub 2008 Mar 3. 
Kurtzke J. Rating Neurologic Impairment in Multiple Sclerosis: an Expanded Disability Status 
Scale (EDSS). Neurology. 1983;33(11):1444-1452. 
Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, et al. Diagnostic criteria for 
multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292–302. 
doi: 10.1002/ana.22366 








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Appendix 3. Patient Global Impression of Change Scale 
 
 
 


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Appendix 4. Columbia–Suicide Severity Rating Scale 








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C-SSRS – Since Last Visit Version 










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Appendix 5. Prohibited Concomitant Medication List 
• Aminoglycoside antibiotics 
• Baclofen 
• Benzodiazepines for anti-spastic indication 
• Botulinum toxin therapy of any serotype 
• Cannabinoids 
• Carisoprodol 
• Chlormezanone 
• Curariform drugs 
• Dalfampridine 
• Dantrolene 
• Gabapentin for anti-spasticity indication 
• Meprobamate 
• Methocarbamol 
• Neuroleptics 
• Orphenadrine 
• Cyclobenzaprine 
• Tizanidine 
• Tolperisone 
 
 
 














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Appendix 8. Summary of Changes 
The following changes have been made to Protocol CLN.OS440-3005.PR.A02.USA as Country-Specific Amendment 2, applicable to 
the United States (US) only: 
SECTION(S) 
CHANGE/RATIONALE 
Entire Document 
Made style and editorial corrections and clarifications, fixed errors, added revised protocol number, and added hyperlinks. 
Title Page 
Added protocol versions history. 
Sections 4.1, 5.1, 6.1 (new), 6.2, 
7.7 and Table 1 footnote 
Changed the Screening duration for de novo subjects from a minimum of 21 days to a maximum of 21 days,  
Section 5.1 
Added the TNmAS-MAL to the inclusion criteria for de novo subjects: “De novo subjects being considered for enrollment 
must have spasticity due to MS as shown by a TNmAS-MAL score ≥2.” 
Section 5.2 
Changed exclusion criterion 12 by replacing “Baseline” with “Screening”: “Subject has clinically significant abnormal 
laboratory values, in the opinion of the investigator at Screening (at Visit 6 for rollover subjects).” 
Section 6.1 (now 6.2), Section 9, 
and Table 1 
Moved the majority of the assessments for de novo subjects from Baseline to Screening: “For de novo subjects being 
considered for enrollment, a Screening visit should occur a maximum of 21 days prior to Baseline to allow for any 
concomitant medication wash-out required for Inclusion Criterion 6.  For de novo subjects, the following procedures will be 
done at this Screening visit: informed consent, inclusion/exclusion criteria, withdrawal of anti-spasticity medication, 
demography, medical/surgical history, physical examination, height, weight, vital signs, hematology/serum 
chemistry/urinalysis, ECG, serum pregnancy test, C-SSRS, TNmAS-MAL, USP, EDSS, and recording of concomitant 
medications.  For de novo subjects, the following assessments and procedures will be performed at the Baseline visit: assign 
enrollment number, vital signs, urine pregnancy test, C-SSRS, TNmAS-MAL, PGIC, USP, dispensing of study medication, 
recording of AEs and concomitant medications, and scheduling/confirmation of the next study visit.” 
Section 6.1 (now 6.2), 6.3 (now 
6.4), 6.5 (now 6.6), Section 8.1, 
and Table 1 footnote 
Removed the Patient Global Impression of Change (PGIC) at Visit 4 (Week 28). 
Sections 7.1.1, 7.9, and 12.4 
Changed the rule requiring subjects who miss 7 or more consecutive days of dosing to be discontinued; the new rule requires 
discontinuation only if the subject misses 7 or more consecutive days of dosing AND has taken less than 80% of their doses 
of study medication in a 42-day (6-week) period. 
Sections 1 and 9.7.3 
Changed name and contact information for one of the Medical Monitors for SAE reporting. 
Appendix 8 
Added new Appendix 8 Summary of Changes to summarize the changes made to the original protocol with Amendment 2. 


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The following changes have been made to Protocol CLN.OS440-3005.PR.A01 as Amendment 1: 
SECTION(S) 
CHANGE/RATIONALE 
Entire Document 
Made editorial corrections and clarifications, fixed errors, added revised protocol number, and added hyperlinks. 
Title Page 
Added protocol versions history. 
Section 9.6.2 
Corrected the mistake in the original protocol regarding a 4-point change in total USP score by replacing “A reduction of 
4 points…” with “An increase of 4 points….” 
Appendix 8 
Added new Appendix 8 Summary of Changes to summarize the changes made to the original protocol with Amendment 1.