Clinical trial NCT03290131
Conditions: Multiple Sclerosis Spasticity, Muscle
Sponsor: RVL Pharmaceuticals, Inc.
Start date: 2018-01-28; Completion date: 2019-01-02
Enrollment: 536 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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. 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, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and efficacy of oral AERT in MS patients with spasticity. Two doses of AERT, 40 mg and 80 mg, will be compared with placebo. The treatment groups will be randomized in a 1:1:1 ratio. Eligible patients will undergo a washout period for withdrawal of all medications used for anti-spasticity and/or muscle relaxation prior to randomization. A baseline clinical evaluation will be performed (Visit 2) to confirm eligibility for study randomization, and subjects will be randomly assigned to 1 of 3 treatment arms. Subjects will remain on maintenance treatment for approximately 3 months.

Arms: arm 1: 40 mg Arbaclofen Extended-Release Tablets arm 2: 80 mg Arbaclofen Extended-Release Tablets arm 3: Placebo
Interventions: intervention 1: Arbaclofen intervention 2: Placebo
Intervention descriptions: intervention 1: Arbaclofen Extended Release Tablet intervention 2: Placebo comparator

Protocol documents:
Prot_000.pdf: 
COVER PAGE 
Document Type:  
 
Study Protocol 
 
 
Document Name:  
 
A Randomized, Double-Blind, Placebo-Controlled Parallel Group Study to Investigate the Safety 
and Efficacy of Arbaclofen Extended-Release Tablets for the Treatment of Spasticity in Patients 
with Multiple Sclerosis (Study OS3440-3004). 
 
 
NCT Number: 
 
NCT03290131 
 
 
Document Date: 
 
09 November 2017 






Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 3 of 76
 
Investigator Protocol Agreement 
Title:  A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Investigate 
the Safety and Efficacy of Arbaclofen Extended-Release Tablets for the Treatment of Spasticity 
in Patients with Multiple Sclerosis (Study OS440-3004) 
 
CONFIDENTIAL 
 
Document Number: CLN.OS440-3004.PR.A02 
 
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:  
 
 
 
 
 
 
 
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 4 of 76
 
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 ..........................................................9 
2 
INTRODUCTION ....................................................................................................10 
2.1 
Multiple Sclerosis and Spasticity ........................................................................10 
3 
STUDY OBJECTIVES ............................................................................................11 
3.1 
Primary Objective ................................................................................................11 
4 
INVESTIGATIONAL PLAN ..................................................................................11 
4.1 
Overall Study Design ...........................................................................................11 
4.2 
Rationale for Study Design and Dose Selection ................................................11 
5 
STUDY POPULATION ...........................................................................................12 
5.1 
Inclusion Criteria .................................................................................................12 
5.2 
Exclusion Criteria ................................................................................................13 
6 
STUDY PROCEDURES ..........................................................................................15 
6.1 
Visit 1 (Screening) – Days –21 to 0 .....................................................................19 
6.2 
Visit 2 (Baseline) – Day 1 (±3 days) ....................................................................20 
6.3 
Visit 3 – Day 10 (±3 days) ....................................................................................21 
6.4 
Visit 4 – Day 42 (±5 days) and Visit 5 – Day 84 (±5 days) ................................21 
6.5 
Visit 6 (Final Visit or Early Termination) – Day 92 (±5 days).........................22 
7 
STUDY TREATMENTS ..........................................................................................23 
7.1 
Treatments Administered ...................................................................................23 
7.1.1 
Treatment Administration ............................................................................23 
7.1.2 
Labeling of Study Drug .................................................................................24 
7.1.3 
Storage of Study Drug ...................................................................................24 
7.2 
Study Drug Accountability..................................................................................24 
7.3 
Handling and Disposal of Study Drug ...............................................................24 
7.4 
Method of Assignment of Study Drug ................................................................25 
7.5 
Selection and Timing of Doses in the Study.......................................................25 
7.6 
Emergency Unblinding ........................................................................................28 
7.7 
Prior and Concomitant Therapy ........................................................................28 
7.8 
Use of Contraception and Pregnancy Testing ...................................................30 
7.9 
Treatment Compliance ........................................................................................30 
8 
EFFICACY ASSESSMENTS ..................................................................................31 
8.1 
Total Numeric-Transformed Modified Ashworth Scale ..................................31 
8.2 
Clinical Global Impression of Change ...............................................................32 
8.3 
Patient Global Impression of Change ................................................................32 
8.4 
Expanded Disability Status Scale .......................................................................33 
9 
SAFETY ASSESSMENTS .......................................................................................33 
9.1 
Medical/Surgical History.....................................................................................33 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 5 of 76
 
9.2 
Vital Signs .............................................................................................................33 
9.3 
Physical Examination ..........................................................................................34 
9.4 
Weight and Height ...............................................................................................34 
9.5 
Clinical Laboratory Tests....................................................................................34 
9.6 
Other Assessments ...............................................................................................35 
9.6.1 
Electrocardiograms........................................................................................35 
9.6.2 
Urinary Symptom Profile© Questionnaire...................................................35 
9.6.3 
Columbia–Suicide Severity Rating Scale .....................................................36 
9.7 
Adverse Events .....................................................................................................36 
9.7.1 
Method of Determining Adverse Events ......................................................36 
9.7.2 
Adverse Event Definitions .............................................................................37 
9.7.2.1 
Adverse Events .........................................................................................37 
9.7.2.2 
Serious Adverse Events ...........................................................................37 
9.7.2.3 
Severity of Adverse Events ......................................................................38 
9.7.2.4 
Relationship of Adverse Events to Study Treatments ..........................38 
9.7.2.5 
Adverse Events Expectedness .................................................................38 
9.7.3 
Reporting Adverse Events .............................................................................39 
9.7.4 
Adverse Event Follow-Up..............................................................................39 
9.7.5 
Pregnancy Reporting .....................................................................................39 
9.8 
Appropriateness of Safety Measurement ...........................................................40 
10 DATA SAFETY MONITORING BOARD ............................................................40 
11 STATISTICAL DESIGN AND ANALYSIS ..........................................................40 
11.1 
Statistical Analysis Plans .....................................................................................40 
11.2 
Analysis Populations ............................................................................................40 
11.3 
Determination of Sample Size .............................................................................41 
11.4 
Efficacy Analyses .................................................................................................41 
11.4.1 
Co-Primary Efficacy Endpoints ...................................................................41 
11.4.2 
Secondary Efficacy Endpoints ......................................................................43 
11.5 
Safety Endpoints ..................................................................................................43 
11.6 
Interim Analysis ...................................................................................................44 
12 STUDY MANAGEMENT........................................................................................44 
12.1 
Monitoring ............................................................................................................44 
12.2 
Protocol Amendments .........................................................................................45 
12.3 
Protocol Deviations ..............................................................................................45 
12.4 
Withdrawal of Subjects .......................................................................................45 
12.5 
Termination of the Study ....................................................................................46 
12.6 
Publication Policy.................................................................................................46 
13 ETHICS .....................................................................................................................46 
13.1 
Conduct of the Study ...........................................................................................46 
13.2 
Institutional Review Boards and/or Independent Ethics Committees ............46 
13.3 
Written Informed Consent ..................................................................................47 
13.4 
Subject Confidentiality ........................................................................................47 
13.5 
Records Retention ................................................................................................48 
13.6 
Financing ..............................................................................................................48 
14 QUALITY CONTROL AND QUALITY ASSURANCE ......................................48 
15 DATA HANDLING AND RECORD KEEPING...................................................48 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 6 of 76
 
16 REFERENCE LIST..................................................................................................50 
APPENDIX 1. 
MODIFIED ASHWORTH SCALE .................................................51 
APPENDIX 2. 
EXPANDED DISABILITY STATUS SCORE ...............................52 
APPENDIX 3. 
CLINICAL GLOBAL IMPRESSION OF CHANGE SCALE ......54 
APPENDIX 4. 
PATIENT GLOBAL IMPRESSION OF CHANGE SCALE ........55 
APPENDIX 5. 
COLUMBIA–SUICIDE SEVERITY RATING SCALE ................56 
C-SSRS – Baseline/Screening Version ...........................................................................56 
C-SSRS – Since Last Visit Version .................................................................................61 
APPENDIX 6. 
PROHIBITED CONCOMITANT MEDICATION LIST ..............66 
APPENDIX 7. 
URINARY SYMPTOM PROFILE QUESTIONNAIRE ...............67 
APPENDIX 8. 
SAFETY REPORTING LINES ...72 
APPENDIX 9. 
SUMMARY OF CHANGES .............................................................75 
 
List of In-Text Tables 
Table 1: 
Schedule of Assessments, Study OS440-3004 ........................................16 
Table 2: 
Study Drug Kits and Treatments, Study OS440-3004 ..........................23 
Table 3: 
Taper and Washout Periods for Specific Anti-spasticity and/or Muscle 
Relaxation Medications, Study OS440-3004..........................................29 
Table 4: 
Clinical Laboratory Tests, Study OS440-3004 ......................................35 
 
List of In-Text Figures 
Figure 1: 
Timeline Diagram, Study OS440-3004 ...................................................18 
Figure 2: 
Flowchart of Blinded Dosing Regimen, Study OS440-3004 .................26 
Figure 3: 
Dosing Schema, Study OS440-3004 ........................................................27 
 
 
 
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 7 of 76
 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
AE 
Adverse event 
AERT 
Arbaclofen extended-release tablets 
ALT 
Alanine transaminase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate transaminase 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CGIC 
Clinical Global Impression of Change 
CRF 
Case report form 
CRO 
Contract Research Organization 
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 
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 
IRT 
Interactive Response Technology (system) 
ITT 
Intent-to-treat (population) 
LOCF 
Last observation carried forward 
LSMeans 
Least-square means 
LUTS 
Lower urinary tract symptoms 
mAS 
Modified Ashworth Scale 
MDRD 
Modification of Diet in Renal Disease Study 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified ITT (population) 
MMRM 
Mixed model for repeated measures 
MS 
Multiple Sclerosis 
mWOCF 
Modified worst observation carried forward 
NARCOMS 
North American Research Committee on MS 
NIMH 
National Institute of Mental Health 
PGIC 
Patient Global Impression of Change 
PK 
Pharmacokinetic 
PMM 
Pattern-mixture model 
PP 
Per-protocol (population) 
PT 
Preferred term 
RBC 
Red blood cell 
RDC 
Remote data capture 
REML 
Restricted maximum likelihood 
RR 
Relapsing-remitting (MS) 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SOC 
System organ class 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 8 of 76
 
Abbreviation 
Definition 
SP 
Secondary-progressive (MS) 
TEAE 
Treatment-emergent adverse event 
TNmAS-MAL 
Total Numeric-transformed mAS score of the most affected limb 
USP 
Urinary Symptom Profile – USP© questionnaire 
WBC 
White blood cell 
WHO 
World Health Organization 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 9 of 76
 
1 
STUDY ADMINISTRATIVE STRUCTURE 
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 10 of 76
 
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 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 11 of 76
 
baclofen and it has been postulated that the efficacy of baclofen is primarily due to the 
R-enantiomer.  This clinical study aims to demonstrate the clinical efficacy and improved 
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 demonstrate the safety and efficacy of arbaclofen 
extended-release tablets (AERT) for treatment of spasticity in patients with MS. 
4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to 
evaluate the safety and efficacy of oral AERT in MS patients with spasticity.  Two doses of 
AERT, 40 mg and 80 mg, will be compared with placebo.  The treatment groups will be 
randomized in a 1:1:1 ratio.  There will be a 9-day titration period, then a 75-day maintenance 
period, followed by a 7-day taper period.  Figure 1 presents the timeline diagram for the study.  
Figure 2 presents the blinded dosing regimen flowchart, including titration and taper doses, to be 
used during the study.  The dosing schema is presented in Figure 3. 
Eligible patients will undergo up to a 21-day washout period for withdrawal of all medications 
used for anti-spasticity and/or muscle relaxation prior to randomization.  A baseline clinical 
evaluation will be performed (Visit 2) to confirm eligibility for study randomization, and 
subjects will be randomly assigned to 1 of 3 treatment arms:  (1) AERT 40 mg; 2) AERT 80 mg; 
or 3) placebo.  During the first 9 days of drug administration, doses will be titrated every 3 days 
to a fixed-dose of either AERT 40 mg, AERT 80 mg, or placebo.  Subjects will remain at that 
fixed-dose for 75 days.  The co-primary efficacy assessments, changes from baseline in the total 
numeric-transformed modified Ashworth Scale score of the most affected limb (TNmAS-MAL) 
and in the Clinical Global Impression of Change (CGIC), will be performed as shown in Table 1.  
At the end of the maintenance period, the subject’s dose will be tapered for an additional 7 days 
before the subject returns to the site for a final safety evaluation at Day 92 (Visit 6).  Table 1 
describes the study visits and timing of all study procedures and assessments. 
4.2 
Rationale for Study Design and Dose Selection 
This study will employ a multicenter, randomized, double-blind, placebo-controlled, parallel-
group study design.  This approach is both methodologically rigorous and considered the gold 
standard in Phase 3 trials in the determination of patient safety and efficacy.  Nonclinical 
arbaclofen data from a 3-month rat toxicity study (Study 0460RO24.001) shows 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, clinically monitorable, and 
reversible, which 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. 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 12 of 76
 
Recently, Osmotica completed a Phase 1, single-center, open-label, multiple-dose, 1-period 
study (Study OS440-PKP09) that assessed the safety, tolerability, and pharmacokinetics (PK) of 
arbaclofen following multiple-dose oral administration of AERT to healthy volunteers in daily 
doses of 40, 60, and 80 mg. 
A total of 24 male and female subjects were enrolled.  The most common TEAE reported was 
dizziness, which is a known adverse reaction to arbaclofen.  No deaths were reported.  Two 
serious adverse events (SAEs) were noted:  Subject 008 (venous thrombosis) and Subject 014 
(haematemesis).  Both SAEs were considered unlikely related to study drug.  AERT was 
tolerated at all doses tested in Study OS440-PKP09.  Increased TEAEs were noted at the 80 mg 
dose; however, they were consistent with the known safety profile of arbaclofen. 
AERT has been shown to be safe in daily doses of 40 and 80 mg, respectively. 
5 
STUDY POPULATION 
Approximately 510 subjects (170 in each treatment group) are planned to be randomized. 
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 (Screening). 
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 
screening. 
3. Spasticity due to MS as shown by a TNmAS-MAL score ≥21 (Appendix 1). 
4. Expanded Disability Status Scale (EDSS) score ≥3.0 (Appendix 2). 
5. If receiving disease-modifying medications (eg, interferons approved for MS, glatiramer 
acetate, natalizumab, fingolimod, or mitoxantrone), there must be no change in dose for 
at least 3 months prior to Visit 1 (Screening), 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 Visit 1 (Screening). 
6. Stable regimen for at least 3 months prior to Visit 2 (Baseline) for all medications and 
non-pharmacological therapies that are intended to alleviate spasticity. 
a. Subjects taking medications indicated for the treatment of spasticity (eg, baclofen, 
benzodiazepines, cannabinoids, carisoprodol, dantrolene, tizanidine, cyclobenzaprine, 
                                                 
1 Total numerical score of a limb accounts for the sum of the 3 main joint muscular group scores. 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 13 of 76
 
any neuroleptic, ropinoprole, tolperisone, and clonidine) at Visit 1 (Screening) must 
wash out from these medications for at most 21 days by Visit 2 (Baseline) in order to 
be eligible for randomization (see Section 7.7 for washout periods for specific 
medications).  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,2 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 and female partners of non-sterile male subjects).  Use of a medically highly 
effective form of birth control (see Section 7.8) during the study and for 3 months 
thereafter for any subject whose partner is not sterilized or post menopausal. 
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. Acute MS exacerbation/relapse requiring treatment or disease modifying drug dose 
alteration within 3 months of Visit 1 (Screening). 
4. Use of high dose (120 mg daily) oral or intravenous methylprednisolone, or equivalent, 
within 3 months before Visit 1 (Screening). 
5. Concomitant use of medications that would potentially interfere with the actions of the 
study medication or outcome variables (Appendix 6). 
6. Use of botulinum toxin A or B for spasticity within 6 months of Visit 1 (Screening). 
                                                 
2 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) 
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 14 of 76
 
7. Pregnancy, lactation, or planned pregnancy during the course of the study and for 
3 months after the final study visit. 
8. Recent history (within past 12 months) of any unstable psychiatric disease (or any yes 
response to questions 1 or 2 on the Columbia–Suicide Severity Rating Scale [C-SSRS] at 
Screening), or current signs and symptoms of significant medical disorders such as severe, 
progressive, or uncontrolled pulmonary, cardiac, 
 hepatic, renal, 
genitourinary, hematological, endocrine, immunologic, or neurological disease. 
9. History of epilepsy. 
10. Current significant cognitive deficit, severe or untreated anxiety, severe or untreated 
depression. 
11. 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 Visit 2 (Baseline) Urinary Symptom Profile – USP© (USP) questionnaire (Appendix 
7).  Subjects who are proficient in self-catheterization may be included in the study at 
investigator discretion. 
12. Subject has clinically significant abnormal laboratory values, in the opinion of the 
investigator, at Visit 1 (Screening). 
13. Current malignancy or history of malignancy that has not been in remission for more than 
5 years, except effectively treated basal cell skin carcinoma. 
14. Any other significant disease, disorder, or significant laboratory finding 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. 
15. Planned elective surgery or other procedures requiring general anesthesia during the 
course of the study. 
16. History of any illicit substance abuse (eg, alcohol, cocaine) or prescription for long-acting 
opioids within the past 12 months (tramadol use will be allowed). 
17. Participation in another clinical research study within 1 month of Visit 1 (Screening). 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 15 of 76
 
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. 
As footnoted in Table 1, the TNmAS-MAL assessment will always be performed by the study 
evaluator (someone other than 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 study evaluator throughout the study.  The 
TNmAS-MAL assessment should be conducted prior to any scheduled study procedures.  The 
most affected limb will be determined by the study evaluator.  The study evaluator must remain 
blinded to the subject’s overall clinical, safety, and CGIC assessments.  The investigator or sub-
investigator will perform the other assessments (EDSS, C-SSRS) and has access to the findings 
of the TNmAS-MAL when conducting the CGIC. 
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 16 of 76
 
Table 1: 
Schedule of Assessments, Study OS440-3004 
Procedure 
Screening 
Visit 1 
Days -21 to 0 
Baseline 
Visit 2 
Day 1 
(±3 days) 
Visit 3 
Day 10 
(±3 days) 
Visit 4 
Day 42 
(±5 days) 
Visit 5 
Day 84 
(±5 days) 
Final or Early 
Termination 
Visit 6 
Day 92 
(±5 days) 
Written informed consent 
X 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
Review study discontinuation criteria 
 
X 
X 
X 
X 
 
Withdrawal anti-spasticity medication 
X 
 
 
 
 
 
Assign enrollment number 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Demography 
X 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
Weight 
X 
 
 
 
 
X 
Vital signs1 
X 
X 
X 
X 
X 
X 
Hematology/serum chemistry/urinalysis 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
X 
 
 
 
 
X 
Pregnancy test2 
X 
X 
X 
X 
X 
X 
Dispense study medication 
 
X 
X 
X 
X 
 
Collect unused study medication 
 
 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
TNmAS-MAL3 
X 
X 
 
X 
X 
X 
EDSS4 
X 
X 
 
 
 
X 
CGIC4 
 
 
 
X 
X 
X 
PGIC 
 
 
 
 
 
X 
USP© questionnaire 
X 
X 
X 
X 
X 
X 
Adverse event assessment 
 
X 
X 
X 
X 
X 
Concomitant medications/therapies 
X 
X 
X 
X 
X 
X 
C-SSRS = Columbia–Suicide Severity Rating Scale; TNmAS-MAL = Total Numeric-transformed modified Ashworth Scale score of the most affected limb; EDSS = Expanded Disability Status 
Scale; CGIC = Clinical Global Impression of Change; PGIC = Patient Global Impression of Change; USP = Urinary Symptom Profile. 
 
(footnotes on next page) 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 17 of 76
 
Table 1 - Footnotes: 
1. Vital signs will be measured with the subject in a supine position and 3 minutes subsequently in a standing position after the supine assessment is 
completed.  Body temperature and respiratory rate will be measured only during the supine assessment. 
2. Premenopausal women of childbearing potential must have a negative serum pregnancy test within 21 days before Visit 2 (Baseline).  Urine pregnancy 
testing will be performed at Visits 2 through 6. 
3. The TNmAS-MAL assessment will be performed prior any scheduled lab draws and will always be done by the study evaluator (someone other than 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 study evaluator throughout the study.  The most affected limb will be determined by the study evaluator. 
4. Performed by the investigator or sub-investigator not functioning as the study evaluator for the particular subject. 
 
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 18 of 76
 
Figure 1: 
Timeline Diagram, Study OS440-3004 
 
 
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 19 of 76
 
6.1 
Visit 1 (Screening) – Days –21 to 0 
Each potential study subject will have a Screening visit (Visit 1) within 21 days prior to 
randomization at the Baseline visit (Visit 2).  At Screening, the investigator will fully explain to 
the subject the objectives, characteristics, and procedures for the study.  Rescreening of subjects 
will only be allowed for delays in screening (eg, >21 days) that have occurred due to technical 
errors (eg, issue with the Interactive Response Technology [IRT] system, or with delivery or 
assessment of laboratory tests, etc).  Screening 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). 
• After establishing the subject’s eligibility to participate, explain to the subject how to 
withdraw all anti-spasticity medication (up to a 21-day period) prior to the next visit 
(Section 7.7). 
• 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). 
• The study evaluator will perform the TNmAS-MAL (Section 8.1). 
• 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.  As per Exclusion Criterion 12, if ,in the 
opinion of the investigator, a subject has clinically significant abnormal laboratory value(s) at 
Visit 1 (Screening), they will be excluded from the study. 
• Perform a standard 12-lead electrocardiogram (ECG) (Section 9.6.1). 
• Collect a blood sample for serum pregnancy testing for women of childbearing potential.  
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). 
• Administer the C-SSRS (Section 9.6.3). 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 20 of 76
 
• Administer the EDSS (Section 8.4). 
• Administer the USP questionnaire (Section 9.6.2). 
• Record all concomitant medications/therapies the subject is currently taking (Section 7.7). 
• Schedule the next visit within approximately 7 to 14 days. 
6.2 
Visit 2 (Baseline) – Day 1 (±3 days) 
This visit takes place after the subject has completed withdrawal of all anti-spasticity 
medications.  Assessments/procedures will include the following: 
• Review eligibility according to the inclusion (Section 5.1) and exclusion criteria (Section 5.2). 
• Review study discontinuation criteria (Section 12.4). 
• Verify complete washout and abstinence from oral anti-spasticity medications for at least the 
past 14 days (Section 7.7). 
• If the subject is eligible for randomization, obtain a randomization code and medication kit 
number for that subject (Section 7.4). 
• The study evaluator will perform the TNmAS-MAL (Section 8.1). 
• 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.  As per Exclusion Criterion 12, if ,in the 
opinion of the investigator, a subject has clinically significant abnormal laboratory value(s) at 
Visit 2 (Baseline), they will be excluded from the study. 
• Collect a urine sample for pregnancy testing for women of childbearing potential 
(Section 7.8). 
• 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. 
• Administer the C-SSRS (Section 9.6.3). 
• Administer the EDSS (Section 8.4). 
• Administer the USP questionnaire (Section 9.6.2). 
• Record any adverse events (AEs) that have occurred (Section 9.7). 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 21 of 76
 
• Record all concomitant medications/therapies the subject is currently taking (Section 7.7). 
• Schedule the next study visit. 
6.3 
Visit 3 – Day 10 (±3 days) 
Assessments/procedures will include the following: 
• Review study discontinuation criteria (Section 12.4). 
• 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). 
• Collect a urine sample for pregnancy testing for women of childbearing potential 
(Section 7.8). 
• 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). 
• Administer the C-SSRS (Section 9.6.3). 
• Administer the USP questionnaire (Section 9.6.2). 
• 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 – Day 42 (±5 days) and Visit 5 – Day 84 (±5 days) 
Assessments/procedures for both visits will include the following: 
• Review study discontinuation criteria (Section 12.4). 
• The study evaluator will perform the TNmAS-MAL (Section 8.1). 
• 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). 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 22 of 76
 
• Collect a urine sample for pregnancy testing for women of childbearing potential 
(Section 7.8). 
• 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). 
• Administer the C-SSRS (Section 9.6.3). 
• Administer the USP questionnaire (Section 9.6.2). 
• Record any AEs that have occurred (Section 9.7). 
• Determination of the CGIC by the Investigator (Section 8.2). 
• Record all concomitant medications/therapies the subject is currently taking (Section 7.7). 
• Schedule the next study visit. 
6.5 
Visit 6 (Final Visit or Early Termination) – Day 92 (±5 days) 
The assessments/procedures listed for Visit 6 (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 Day 92 due to early termination of the subject, every effort 
should be made to perform the clinical evaluations as follows, especially the blood sampling for 
hematology, serum chemistry, and urinalysis, and the ECG.  Assessments/procedures will 
include the following: 
• Record weight (Section 9.4). 
• The study evaluator will perform the TNmAS-MAL (Section 8.1). 
• 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). 
• Collect unused study medication, assess compliance, and study drug accountability 
(Section 7.9). 




Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 24 of 76
 
drug for greater than 5 consecutive days must be withdrawn from the study and followed for 
safety (Section 12.4). 
7.1.2 
Labeling of Study Drug 
Double-blind study medication will be provided in blister card wallets.  The labels will include 
all information required by federal and local regulations. 
7.1.3 
Storage of Study Drug 
Arbaclofen extended-release tablets and matching placebo tablets must be stored at 25°C (77°F); 
excursions permitted to 15-30°C (59-86°F) (see USP Controlled Room Temperature).  Study 
medication should be protected from moisture and humidity.  At study sites, all study medication 
must be stored, secured, and locked in a safe place. 
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 (eg, 
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 (eg, 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 (eg, in a locked storage facility). 
Any unused, partially used, or empty blister card wallets 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. 
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 25 of 76
 
7.4 
Method of Assignment of Study Drug 
Two doses of AERT, 40 mg (20 mg BID) and 80 mg (40 mg BID), will be compared with 
placebo.  The treatment groups will be randomized in a 1:1:1 ratio. 
After Screening 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.  After 
the Screening clinical laboratory test results and other clinical assessments have been completed 
at Visit 2 (Baseline), assignment to a treatment group will then follow a predetermined list of 
randomization numbers, with each successive number receiving 1 of the 3 treatments in random 
order.  Authorized site personnel will use the IRT system to assign a kit number that corresponds 
to the randomization schedule.  The kit box with the assigned kit number will be dispensed to the 
subject. 
The randomization code will be provided by the CRO. 
7.5 
Selection and Timing of Doses in the Study 
There will be a 9-day titration period, then a 75-day maintenance period, followed by a 7-day 
taper period.  Figure 2 presents the dosing regimen flowchart, including titration and taper doses, 
to be used during the study.  The dosing schema is presented in Figure 3. 
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 26 of 76
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 27 of 76
 
Figure 3: 
Dosing Schema, Study OS440-3004 
 
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 28 of 76
 
7.6 
Emergency Unblinding 
This is a double-blind study.  Every effort will be made to retain the integrity of the blind.  The 
study drug will be identical in appearance for all subjects, regardless of treatment assignment, by 
using over-encapsulation of the different tablet strengths. 
In the event that emergency identification of study drug is required (eg, if the Investigator 
believes that the information is necessary to properly treat a subject with an AE), the study drug 
identity can be obtained by the investigator directly accessing the IRT system.  The subject 
should be informed of the treatment assignment. 
Every effort must be made to alert the Medical Monitor before requesting that the blind be 
broken.  If this is not possible, the Medical Monitor should be immediately notified of the 
breaking of the blind.  The Investigator will record the unblinding procedures in the subject’s 
source documents. 
If unblinding is necessary, the subject will be withdrawn from the study and Visit 6 (Final or 
Early Termination Visit) procedures will be completed. 
The study blind will be broken at study completion once the following are met: 
• Database is locked 
• The statistical analysis plan (SAP) is finalized 
Once the decision for unblinding is reached, the study team will prepare an unblinding memo 
with signatures from the study director and sponsor biostatistician. 
7.7 
Prior and Concomitant Therapy 
The inclusion and exclusion criteria (Section 5.1 and Section 5.2, respectively) provide details on 
prohibited medications and the permitted duration since their last use prior to Screening and/or 
study drug administration.  All medications taken within 90 days before Visit 2/Baseline 
(randomization) are to be recorded in the CRF/eCRF.  Eligible patients will undergo up to a 
21-day washout period (no drug onboard) for withdrawal of all medications used for anti-
spasticity and/or muscle relaxation prior to randomization (see Inclusion Criterion 6).  Subjects 
will be ineligible for randomization if they concomitantly use any of the medications listed in 
Appendix 6 (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. 
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 29 of 76
 
Table 3: 
Taper and Washout Periods for Specific Anti-spasticity and/or 
Muscle Relaxation Medications, Study OS440-3004 
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 
All conventional medications regularly used for the treatment of MS, other than anti-spasticity 
medications, and non-pharmacological therapies (intended to alleviate spasticity, eg, 
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. 
Ancillary therapy for spasticity such as hydrotherapy, massage, and acupuncture are allowed 
however, the administration and frequency must be consistent for at least 3 months prior to 
Screening and throughout the duration of participation in the study.  Any deviation from this 
ancillary therapy is grounds for subject withdrawal. 
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 (eg, 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 CRF/eCRF.  If there 
is any question, the Medical Monitor must be contacted. 
Data collection for concomitant medications will include indication, dose, route, dosing 
frequency, start date, stop date, and will continue throughout the study. 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 30 of 76
 
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/therapies since the last study 
visit.  It is the responsibility of the Investigator to ensure that any change in concomitant 
medications/therapies during the study is recorded in the source documentation and entered in 
the CRF/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).  Premenopausal women of 
childbearing potential must have a negative serum pregnancy test within 21 days before Visit 2 
(Baseline) and, 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 2 through 6. 
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 
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 as 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 31 of 76
 
assessed by the amount of study drug returned by the subject.  Dose interruption for more than 
5 consecutive days during the titration or maintenance periods will require early study 
withdrawal of the subject. 
8 
EFFICACY ASSESSMENTS 
8.1 
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. 
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 a limb accounts for the sum of 
the 3 main joint muscular group scores.  If two or more limbs tie for “Most Affected” at Visit 2 
(Baseline), then the Visit 5 (Day 84) scores for the tied limbs will be assessed and the one with 
the worst score at Visit 5 will become the MAL in the primary analysis.  In the case of a tie at 
Visit 2 (Baseline) and at Visit 5, then all of the scores from Visit 2 to Visit 5 will be summed and 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 32 of 76
 
the highest (worst) total will be flagged as the MAL.  If a subject discontinues early, then the 
early termination visit scores will be used in place of the Visit 5 scores. 
The TNmAS-MAL assessment will always be performed by the study evaluator (someone other 
than 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 study evaluator throughout the study prior to any scheduled lab draw.  The 
most affected limb will be determined by the study evaluator and the subject.  The study 
evaluator must remain blinded to the subject’s overall clinical, safety, and CGIC assessments. 
The TNmAS-MAL assessment will be done at the visits specified in Table 1.  The mAS and 
TNmAS-MAL are provided in Appendix 1. 
8.2 
Clinical Global Impression of Change 
The CGIC was developed for use in National Institute of Mental Health (NIMH)-sponsored 
clinical trials to provide a brief, stand-alone assessment of the clinician’s view of the subject’s 
global functioning prior to and after initiating a study medication (Guy 1976).  The CGIC scale 
will be used to measure the overall change in the subject’s condition since starting the study. 
In clinical research, the CGIC is administered by an experienced clinician who is familiar with 
the disease under study and the likely progression of treatment.  Consequently, the CGIC rater 
can make an expert clinical global judgment about the severity of the illness across various time 
points within the context of that clinical experience.  The clinician makes a judgment about the 
total picture of the subject at each visit:  the illness severity, the subject’s level of distress and 
other aspects of impairment, and the impact of the illness on functioning.  The CGIC is rated 
without regard to the clinician’s belief that any clinical changes are or are not due to medication 
and without consideration of the etiology of the symptoms. 
The investigator will evaluate the subject’s status on a -3 to +3 scale judging whether there had 
been a change from significant worsening to significant improvement relative to Visit 2 
(Baseline) and must have access to the TNmAS.  The CGIC scale is provided in Appendix 3. 
8.3 
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 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 33 of 76
 
• 6 = Much worse 
• 7 = Very much worse 
The PGIC will be done at the visits specified in Table 1.  The PGIC is provided in Appendix 4. 
8.4 
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.  Scoring is based on an examination by a 
neurologist. 
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 TEAEs volunteered, observed, and elicited by 
general questioning in a non-suggestive manner.  Changes in vital signs, clinical laboratory test 
results, 12-lead electrocardiograms (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 Visit 1 (Screening), which will 
record previous respiratory, cardiovascular, gastrointestinal, hepatic, nephro-urologic, metabolic, 
allergic, 
infectious, 
gynecologic, 
musculoskeletal, 
endocrine, 
neurologic, 
psychiatric, 
dermatologic, allergic, hematologic, and any other diseases. 
9.2 
Vital Signs 
Heart rate and BP 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 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 34 of 76
 
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 Visit 1 (Screening) and will include the following 
categories:  general, head, ears, eyes, nose and throat, neck, 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 Visit 1 (Screening) and at Visit 6 (Final Visit or Early Termination).  
Height will only be measured at Visit 1 (Screening).  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/CRF. 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 35 of 76
 
Table 4: 
Clinical Laboratory Tests, Study OS440-3004 
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 
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 Screening). 
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 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 by 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 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 36 of 76
 
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 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 7. 
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 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 5. 
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 CRF/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. 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 37 of 76
 
• 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. 
• 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 
A “serious adverse event” (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). 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 38 of 76
 
• 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: 
• 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. 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 39 of 76
 
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: 
  
 
 
  
 
 
9.7.4 
Adverse Event Follow-Up 
Adverse events that are ongoing when a subject withdraws from or completes the study will be 
followed until resolution or stabilization (in the opinion of the Investigator), or for 30 days, 
whichever is shorter.  Investigators and the Sponsor will decide if longer follow-up is appropriate 
on a case-by-case basis.  Subjects who experience any clinically significant AE will remain 
under medical supervision until the Investigator or the Sponsor’s Medical Monitor deems the AE 
to be resolved, stabilized, or no longer serious enough to warrant follow-up. 
Laboratory values that are abnormal and not assessed as AEs may be followed at the discretion 
of the Investigator or the Sponsor’s Medical Monitor until resolved or stabilized. 
9.7.5 
Pregnancy Reporting 
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.  The ICF that the subject signs must 
document this discussion. 
If a subject or Investigator suspects that the subject may be pregnant prior to study drug 
administration, the study drug must be withheld until the results of laboratory pregnancy testing 
are available.  If pregnancy is confirmed, the subject must not receive study drug and must not be 
enrolled in the study. 
A urine pregnancy test will be performed on all females of childbearing potential as described in 
Section 7.8. 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 40 of 76
 
During the study, all female subjects of childbearing potential should be instructed to contact the 
Investigator immediately if they suspect they might be pregnant (eg, missed or late menstrual 
period).  If a subject or Investigator suspects that the subject may be pregnant at any time before 
or during the study, the study drug must be withheld until the results of laboratory pregnancy 
testing are available.  The Sponsor and site monitor must be notified and relevant information 
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 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.  The final DSMB Charter, pending review and approval by the DSMB at the 
initial meeting, is in a separate document. 
11 STATISTICAL DESIGN AND ANALYSIS 
11.1 
Statistical Analysis Plans 
A detailed SAP will be finalized prior to breaking of the study blind. 
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.  Hypothesis testing will be performed for the co-primary and other selected efficacy 
endpoints.  Unless specified otherwise, all statistical testing will be two-sided and performed 
using a significance level of 0.05. 
11.2 
Analysis Populations 
The populations defined for analysis will include the following: 
• Intent-to-Treat (ITT) population:  Includes all subjects who are randomized.  The 
ITT population will be used for analyses of accountability, demographics, baseline 
characteristics, and efficacy. 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 41 of 76
 
• Modified ITT (mITT) population:  Includes the ITT population minus any subjects with MS 
relapse.  This will be a secondary supporting population for the co-primary efficacy analyses. 
• Safety population:  Includes all subjects who receive at least one dose of double-blind 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 analyses. 
• Per-Protocol (PP) population:  Includes all subjects who complete study treatment and have 
no significant protocol deviations.  This will be a secondary supporting population for the 
co-primary efficacy analyses. 
11.3 
Determination of Sample Size 
11.4 
Efficacy Analyses 
11.4.1 
Co-Primary Efficacy Endpoints 
The AERT 40 mg dose will be compared with placebo first (for both TNmAS-MAL and CGIC).  
If both comparisons are significant at the 0.05 level then the AERT 80 mg dose will be tested at 
the 0.05 level (both TNmAS-MAL and CGIC).  Both co-primary efficacy endpoints need to meet 
the 0.05 level for the AERT 40 mg dose comparison with placebo for the study to be considered 
a success.  Therefore, no adjustment for multiplicity is needed.  The Day 84 comparison is the 
primary time point for both co-primary endpoints. 
Descriptive statistics for each co-primary efficacy variable will be tabulated by study visit and 
treatment group.  CGIC categories will also be summarized by frequencies and percentages by 
study visit and treatment group. 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 42 of 76
 
TNmAS-MAL will be analyzed using a restricted maximum likelihood (REML)-based mixed 
model for repeated measures (MMRM) with fixed effects for treatment, visit, study center, and 
the treatment-by-visit interaction; and with baseline score as a covariate.  The outcome variable 
will be change from baseline scores.  Study visit will be included in the model as a categorical 
variable (Visit 4 [Day 42] and Visit 5 [Day 84]) along with the treatment-by-visit interaction.  
Least squares means (LS means) will be used to compare treatments. 
CGIC will also be analyzed using an REML-based MMRM with fixed effects for treatment, visit, 
study center, and the treatment-by-visit interaction.  As the CGIC is a change score, no value is 
measured at baseline.  The outcome variable will be CGIC scores.  Study visit will be included in 
the model as a categorical variable (Visit 4 [Day 42] and Visit 5 [Day 84]) along with the 
treatment-by-visit interaction.  LS means will be used to compare treatments. 
For both models, pairwise treatment comparisons between the two AERT doses and placebo will 
be performed at each visit; however, the primary comparisons will be the contrasts between 
AERT 40 mg dose and placebo at Day 84.  Unstructured covariance matrices will be utilized and 
study centers may be pooled prior to unblinding. 
A number of sensitivity analyses will be performed to assess the robustness of the results of the 
primary analyses and to test the assumptions of the MMRM model.  A complete description of 
the analyses will be provided in the SAP.  Details of statistical methods for these sensitivity 
analyses are briefly described below: 
• The primary efficacy analyses will be repeated using the mITT and PP populations. 
• Separate models including treatment-by-study center will be utilized to assess if treatment 
effects differ by study center. 
• To determine if the primary efficacy results are affected by subjects who withdraw early 
from the trial, the TNmAS-MAL and CGIC scores for subjects who withdraw from the trial 
early will be compared with the scores for subjects who completed the trial.  The last 
observed TNmAS-MAL and CGIC score captured prior to early termination will be plotted 
and compared against the average TNmAS-MAL and CGIC scores calculated from subjects 
who complete the trial. 
• To ensure that subjects who withdraw early from the trial with “good” TNmAS-MAL and 
CGIC scores do not unduly bias the results of the primary efficacy analyses in a positive 
direction, subjects who withdraw early from the trial will be penalized.  In this analysis, 
subjects will be penalized for withdrawing early from the trial with a “good” TNmAS-MAL 
or CGIC score and based on the amount of time the subject was in the trial, with subjects 
who withdraw from the trial being penalized more. 
• The impact of missing data will be determined in an analysis using an analysis of covariance 
(ANCOVA) model based on modified worst observation carried forward (mWOCF) imputed 
data.  For mWOCF imputed data, subjects who withdraw from the trial early due to an AE 
will have their missing data imputed using WOCF, all other missing data will be imputed 
using the last observation carried forward (LOCF).  The models will include treatment and 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 43 of 76
 
study site as fixed effects.  The model for TNmAS will also include baseline score as a 
covariate. 
• The primary efficacy analysis model (MMRM) makes the assumption that missing data are 
“missing at random.”  The robustness of this assumption will be tested using a pattern-
mixture model (PMM).  Pattern-mixture modeling addresses data that may be “missing not at 
random” by estimating parameters within each pattern and then averaging these parameter 
estimates across patterns for the final inference. 
11.4.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include: 
• EDSS 
• PGIC 
• TNmAS – Total Limbs 
Secondary efficacy endpoints will be summarized descriptively and analyzed using the same 
type of MMRM analysis used for the co-primary efficacy endpoints.  Pairwise comparisons 
between the AERT doses and placebo will be provided at each visit where data are collected.  
Additional factors along with interaction terms may be included in the models as sensitivity 
analyses.  Details will be provided in the SAP. 
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.  Summaries of 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. 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 44 of 76
 
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 CRF/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, CRFs/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. 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 45 of 76
 
12.2 
Protocol Amendments 
The Sponsor may propose to amend this protocol at any time. 
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.  A subject will be considered to have discontinued prematurely if he/she withdraws 
after being randomized and prior to completing Visit 6 (Final Visit).  Subjects who discontinue 
taking study drug for any reason for greater than 5 consecutive days must also be withdrawn 
from the study.  Subjects may 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:  As per the comprehensive lost to follow-up guidance document that will 
be submitted to the IRB/IEC with the clinical protocol. 
• Subject Request:  Subject requests for any reason to be withdrawn or withdraws his/her 
consent. 
• 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. 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 46 of 76
 
• 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 (eg, oral or intravenous high-
dose steroid therapy).  Upon resolution of symptoms, the subject may choose to be assessed 
for entry into the subsequent open-label extension study (Study OS440-3005). 
• 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 6 
assessments (Table 1).  The reason(s) for early withdrawal must be recorded in the CRF/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 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 47 of 76
 
IRB/IEC at the time initial approval is sought must include any plans for subject recruitment that 
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 (ie, 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. 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 48 of 76
 
13.5 
Records Retention 
The Investigator must maintain essential study documents (protocol and amendments, source 
documentation corresponding to all information contained in the CRFs/eCRFs, signed ICFs, 
relevant 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 CRFs/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, electronic case report forms (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 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 49 of 76
 
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 database (eg, 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 (eg, obvious errors in dates). 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 50 of 76
 
16 REFERENCE LIST 
Ashworth B. Preliminary Trial of Carisoprodol in Multiple Sclerosis. Practitioner. 
1964;192:540-542. 
Bohannon RW, Smith MB. Inter-rater reliability of a modified Ashworth scale of muscle 
spasticity. Physical Therapy. 1987;67:206-207. 
Guy W. Assessment Manual for Psychopharmacology-Revised. Rockville, MD: Department 
of Health, Education and Welfare Public Health Service, Alcohol, Drug Abuse, and Mental 
Health Administration, NIMH Psychopharmacology Research Branch, Division of 
Extramural Research Programs. 1976:218-222. 
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. 
 
 
 
 
 
 










Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 55 of 76
 
Appendix 4. Patient Global Impression of Change Scale 
 
 
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 56 of 76
 
Appendix 5. Columbia–Suicide Severity Rating Scale 
C-SSRS – Baseline/Screening Version 
 
COLUMBIA-SUICIDE SEVERITY  
RATING SCALE  
(C-SSRS)  
Baseline/Screening Version  
Version 1/14/09  


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 57 of 76
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 58 of 76
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 59 of 76
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 60 of 76
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 61 of 76
 
C-SSRS – Since Last Visit Version 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit Version 1/14/09 
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 62 of 76
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 63 of 76
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 64 of 76
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 65 of 76
 
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 66 of 76
 
Appendix 6. Prohibited Concomitant Medication List 
• Aminoglycoside antibiotics 
• Baclofen 
• Benzodiazepines 
• Botulinum toxin therapy of any serotype 
• Cannabinoids 
• Carisoprodol 
• Chlormezanone 
• Curariform drugs 
• Dalfampridine 
• Dantrolene 
• Gabapentin for anti-spasticity indication 
• Meprobamate 
• Methocarbamol 
• Neuroleptics such as tricyclic antidepressants and narcotics 
• Orphenadrine 
• Cyclobenzaprine 
• Tizanidine 
• Tolperisone 
 
 






Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 69 of 76
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 70 of 76
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 71 of 76
 




Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 73 of 76
 
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 74 of 76
 
 
 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 75 of 76
 
Appendix 9. Summary of Changes 


Study OS440-3004 
Osmotica Pharmaceutical US LLC
Arbaclofen extended-release tablets 
CLN.OS440-3004.PR.A02 
CONFIDENTIAL 
Page 76 of 76
 

SAP_001.pdf: 
COVER PAGE 
Document Type:  
 
Statistical Analysis Plan 
 
 
Document Name:  
 
A Randomized, Double-Blind, Placebo-Controlled Parallel Group Study to Investigate the Safety 
and Efficacy of Arbaclofen Extended-Release Tablets for the Treatment of Spasticity in Patients 
with Multiple Sclerosis (Study OS3440-3004). 
 
 
NCT Number: 
 
NCT03290131 
 
 
Document Date: 
 
28 January 2019 




Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                    
CONFIDENTIAL 
 
P a g e  | 2 
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 
4.2. 
Study Endpoints ................................................................................................................................ 7 
4.2.1. 
Primary Endpoint ............................................................................................................ 7 
4.2.2. 
Secondary Endpoints ....................................................................................................... 7 
5. 
STUDY METHODS ...................................................................................................................................... 8 
5.1. 
General Study Design and Plan......................................................................................................... 8 
5.2. 
Randomization and Blinding........................................................................................................... 12 
5.3. 
Analysis Variables .......................................................................................................................... 12 
6. 
SAMPLE SIZE ............................................................................................................................................ 12 
7. 
GENERAL CONSIDERATIONS ............................................................................................................... 13 
7.1. 
Analysis Populations ....................................................................................................................... 13 
7.1.1. 
Screened Population (SCREEN) ................................................................................... 13 
7.1.2. 
Intent-to-Treat Population (ITT) ................................................................................... 13 
7.1.3. 
Modified Intent-to-Treat Population (mITT) ................................................................ 13 
7.1.4. 
Per-Protocol Population (PP) ........................................................................................ 13 
7.1.5. 
Safety Population (SP) .................................................................................................. 13 
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 ......................................................................................................... 16 
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 
7.5. 
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 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                    
CONFIDENTIAL 
 
P a g e  | 3 
8.4. 
Medical and Surgical History.......................................................................................................... 18 
8.5. 
Prior and Concurrent Medications .................................................................................................. 19 
8.6. 
Treatment Compliance .................................................................................................................... 19 
9. 
EFFICACY ANALYSES ............................................................................................................................ 20 
9.1. 
Primary Efficacy ............................................................................................................................. 20 
9.1.1. 
Co-Primary Efficacy Endpoints .................................................................................... 20 
9.1.2. 
Co-Primary Efficacy Analyses ...................................................................................... 20 
9.1.3. 
Co-Primary Efficacy Sensitivity Analyses .................................................................... 21 
9.2. 
Secondary Efficacy ......................................................................................................................... 23 
9.2.1. 
Secondary Efficacy Endpoints ...................................................................................... 23 
9.2.2. 
Secondary Efficacy Analyses ........................................................................................ 24 
10. SAFETY ANALYSES................................................................................................................................. 24 
10.1. 
Adverse Events ............................................................................................................................... 24 
10.2. 
Deaths, Serious Adverse Events and Other Significant Adverse Events ........................................ 25 
10.2.1. 
Deaths............................................................................................................................ 25 
10.2.2. 
Serious Adverse Events ................................................................................................. 25 
10.2.3. 
Adverse Events Leading to Discontinuation of Study Drug ......................................... 25 
10.3. 
Clinical Laboratory Evaluations ..................................................................................................... 25 
10.4. 
Vital Signs ....................................................................................................................................... 25 
10.5. 
Physical Examinations .................................................................................................................... 26 
10.6. 
Other Safety Measures .................................................................................................................... 26 
11 
REPORTING CONVENTIONS .................................................................................................................. 26 
11.1 
General Reporting Conventions ...................................................................................................... 26 
11.2 
Population Summary Conventions .................................................................................................. 27 
12 
REFERENCES ............................................................................................................................................ 28 
 
 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                    
CONFIDENTIAL 
 
P a g e  | 4 
 
LIST OF TABLES 
 
Table 1 
Schedule of Assessments .............................................................................................. 10 
 
 
LIST OF FIGURES 
 
Figure 1 
Study Design Schema ..................................................................................................... 9 
Figure 2 
SDTM, ADaM, and TFL Development and Validation ................................................ 16 
 
 
 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                    
CONFIDENTIAL 
 
P a g e  | 5 
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 
ANCOVA 
Analysis of covariance 
CDISC 
Clinical Data Interchange Standards Consortium 
CGIC 
Clinical Global Impression of Change 
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) 
ITT 
Intent-to-treat (population) 
LOCF 
Last observation carried forward 
LS Means 
Least-squares means 
mAS 
Modified Ashworth Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified ITT (population) 
MMRM 
Mixed model for repeated measures 
MS 
Multiple Sclerosis 
mWOCF 
Modified worst observation carried forward 
PGIC 
Patient Global Impression of Change 
PMM 
Pattern-mixture model 
PP 
Per-protocol (population) 
PT 
Preferred term 
REML 
Restricted maximum likelihood 
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 mAS score of the most affected limb 
USP 
Urinary Symptom Profile - USP© questionnaire 
WHO 
World Health Organization 
WHO-DD 
World Health Organization – Drug Dictionary 
 
 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                    
CONFIDENTIAL 
 
P a g e  | 6 
3. 
INTRODUCTION 
3.1. 
Preface 
This document presents a statistical analysis plan (SAP) for Osmotica Pharmaceutical’s 
Protocol OS440-3004 (A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Investigate the Safety and Efficacy of Arbaclofen Extended-Release Tablets for the 
Treatment of Spasticity in Patients with Multiple Sclerosis). 
Reference materials for this statistical plan includes the protocol OS440-3004 (CLN.OS440-
3004.PR.A01Dated: 19 SEP 2017). 
The SAP described hereafter is an a priori plan.  The SAP will be finalized and approved 
prior to unblinding of any study data.  Statistical programming may occur as study data 
accumulate in order to have analysis programs ready at the time the study finishes.  In such 
an event, arbitrary treatment group assignments must be randomly linked to subjects, 
effectively rendering any output of programs meaningless.   
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 patients with spasticity.  
Results from the analyses completed will be included in the final clinical study report for 
OS440-3004, 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. 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                    
CONFIDENTIAL 
 
P a g e  | 7 
4. 
STUDY OBJECTIVES AND ENDPOINTS 
4.1. 
Study Objectives 
4.1.1. 
Primary Objective 
The primary objective of this study is to demonstrate the safety and efficacy of arbaclofen 
extended-release tablets (AERT) for treatment of spasticity in patients with MS. 
4.2. 
Study Endpoints 
4.2.1. 
Primary Endpoint 
The co-primary efficacy endpoints include the following: 
• Total Numeric-Transformed Modified Ashworth Score – Most Affected Limb 
(TNmAS-MAL) 
• Clinical Global Impression of Change (CGIC) 
4.2.2. 
Secondary Endpoints 
Secondary endpoints include the following: 
Safety and Tolerability: 
• Adverse events  
• Vital signs 
• Clinical laboratory tests 
• 12-lead electrocardiograms (ECGs) 
• Urinary Symptom Profile - USP© questionnaire (USP) 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Efficacy: 
• Patient Global Impression of Change (PGIC) 
• Expanded Disability Status Scale (EDSS) 
• TNmAS – Total Limbs (TNmAS-TL) 
 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                    
CONFIDENTIAL 
 
P a g e  | 8 
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, randomized, double-blind, placebo-controlled, parallel-group study to 
evaluate the safety and efficacy of oral AERT in MS patients with spasticity.  Two doses of 
AERT, 40 mg and 80 mg, will be compared with placebo.  The treatment groups will be 
randomized in a 1:1:1 ratio.  There will be a 9-day titration period, then a 75-day 
maintenance period, followed by a 7-day taper period.       
Eligible subjects will undergo an at least 14-day washout period for withdrawal of all 
medications used for anti-spasticity and/or muscle relaxation prior to randomization.  A 
baseline clinical evaluation will be performed (Visit 2) to confirm eligibility for study 
randomization, and subjects will be assigned to 1 of 3 treatment arms: (1) AERT 40 mg; 2) 
AERT 80 mg; or 3) placebo.  During the first 9 days of drug administration, doses will be 
titrated about every 3 days to a fixed-dose of either AERT 40 mg, AERT 80 mg, or placebo 
BID.  Subjects will remain at that fixed-dose for 75 days.  At the end of the maintenance 
period, the subject’s dose will be tapered for an additional 7 days before the subject returns to 
the site for a final safety evaluation at Day 92 (Visit 6). 
The study design schema is presented in Figure 1.  The schedule for assessments is presented 
in Table 1. 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                    
CONFIDENTIAL 
 
P a g e  | 9 
Figure 1 
Study Design Schema 
 
 
 


Osmotica Pharmaceutical                                                                                                                   CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan  
CONFIDENTIAL 
 
P a g e  | 10 
Table 1 
Schedule of Assessments 
 
Procedure 
Screening 
Visit 1 
Days -21 to 0 
Baseline 
Visit 2 
Day 1 
(±3 days) 
Visit 3 
Day 10 
(±3 days) 
Visit 4 
Day 42 
(±5 days) 
Visit 5 
Day 84 
(±5 days) 
Final or Early 
Termination 
Visit 6 
Day 92 
(±5 days) 
Written informed consent 
X 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
Review study discontinuation criteria 
 
X 
X 
X 
X 
 
Withdrawal anti-spasticity medication 
X 
 
 
 
 
 
Assign enrollment number 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Demography 
X 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
Weight 
X 
 
 
 
 
X 
Vital signs1 
X 
X 
X 
X 
X 
X 
Hematology/serum chemistry/urinalysis 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
X 
 
 
 
 
X 
Pregnancy test2 
X 
X 
X 
X 
X 
X 
Dispense study medication 
 
X 
X 
X 
X 
 
Collect unused study medication 
 
 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
TNmAS-MAL3 
X 
X 
 
X 
X 
X 
EDSS 
X 
X 
 
 
 
X 
CGIC 
 
 
 
X 
X 
X 
PGIC 
 
 
 
 
 
X 
USP© questionnaire 
X 
X 
X 
X 
X 
X 
Adverse event assessment 
 
X 
X 
X 
X 
X 
Concomitant medications/therapies 
X 
X 
X 
X 
X 
X 
C-SSRS = Columbia–Suicide Severity Rating Scale; TNmAS-MAL = Total Numeric-transformed modified Ashworth Scale score of the most affected limb; EDSS = Expanded Disability Status 
Scale; CGIC = Clinical Global Impression of Change; PGIC = Patient Global Impression of Change; USP = Urinary Symptom Profile. 


Osmotica Pharmaceutical                                                                                                                   CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan  
CONFIDENTIAL 
 
P a g e  | 11 
 
Table 1 - Footnotes: 
1. Vital signs will be measured with the subject in a supine position and in a standing position 3 minute after the supine assessment is completed.  
Body temperature and respiratory rate will be measured only during the supine assessment. 
2. Premenopausal women of childbearing potential must have a negative serum pregnancy test within 28 days before Visit 2 (Baseline).  Urine 
pregnancy testing will be done at Visits 2 through 6. 
3. The TNmAS-MAL assessment will be performed prior any scheduled lab draws and will always be done by the study evaluator (someone other 
than 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 study evaluator throughout the study.  The most affected limb will be 
determined by the study evaluator. 
4. Performed by the investigator or sub-investigator not functioning as the study evaluator for the particular subject. 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                       
CONFIDENTIAL 
 
P a g e  | 12 
 
5.2. 
Randomization and Blinding 
Two doses of AERT, 40 mg (20 mg BID) and 80 mg (40 mg BID), will be compared with 
placebo.  The treatment groups will be randomized in a 1:1:1 ratio.  The randomization 
schedule will be stratified by geographic region: Eastern Europe, Central Europe, and North 
America. 
After Screening procedures have been completed at Visit 1, authorized site personnel will 
acknowledge that the applicable subject met all the specified inclusion criteria and none of 
the exclusion criteria and an enrollment number will be sequentially assigned.  After the 
Screening clinical laboratory test results and other clinical assessments have been completed 
at Visit 2 (Baseline), assignment to a treatment group will then follow a predetermined list of 
randomization numbers, with each successive number receiving 1 of the 3 treatments in 
random order.  Authorized site personnel will use the Interactive Response Technology (IRT) 
system to assign a kit number that corresponds to the randomization schedule.  The kit box 
with the assigned kit number will be dispensed to the subject. 
The randomization code will be provided by the Sponsor. 
5.3. 
Analysis Variables 
Variables to be analyzed include demographics and baseline characteristics, safety variables 
(adverse events, clinical laboratory investigations, vital signs, ECGs, USP questionnaire, and 
C-SSRS), and efficacy variables (TNmAS-MAL, CGIC, PGIC, EDSS, and TNmAS-TL). 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 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                       
CONFIDENTIAL 
 
P a g e  | 13 
 
7. 
GENERAL CONSIDERATIONS 
7.1. 
Analysis Populations 
There will be five (5) 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, regardless of participation. 
7.1.2. 
Intent-to-Treat Population (ITT) 
Includes all subjects who are randomized.  Subjects included in the ITT population will be 
analyzed as randomized.  The ITT population will be used for analyses of accountability, 
demographics, baseline characteristics, and efficacy. 
7.1.3. 
Modified Intent-to-Treat Population (mITT) 
Includes the ITT population minus any subjects with MS relapse.  Subjects in the mITT 
population will be analyzed as randomized.  This will be a secondary supporting population 
for the co-primary efficacy analyses. 
7.1.4. 
Per-Protocol Population (PP) 
Includes all subjects who complete study treatment and have no significant protocol 
deviations.  Subjects who are members of the PP population will be analyzed as randomized. 
This will be a secondary supporting population for the co-primary efficacy analyses. 
7.1.5. 
Safety Population (SP) 
Includes all subjects who receive at least one dose of double-blind study treatment and have 
at least one post-dose visit.  Subjects who are members of the safety population will be 
analyzed according to the treatment received.  This population will be used for all safety 
analyses. 
 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                       
CONFIDENTIAL 
 
P a g e  | 14 
 
7.2. 
Covariates and Subgroups 
7.2.1. 
Planned Covariates 
The efficacy analyses will include study center as an effect and baseline values (where 
applicable) as a covariate.  Other covariates may be used for exploratory analyses. 
7.2.2. 
Planned Subgroups 
The co-primary efficacy endpoints will be summarized with descriptive statistics for the 
following subgroups: study center, duration of MS, presence or absence of disease modifying 
agents, class of anti-spasticity agent, prior baclofen use, baseline EDSS score, and age.  
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: 
i) If the year matches the first dose date year, then impute 
the month and day of the first dose date. 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                       
CONFIDENTIAL 
 
P a g e  | 15 
 
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 the majority of analyses.  A modified 
worst observation carried forward (mWOCF) imputation method will be utilized in a 
sensitivity analysis for the co-primary efficacy endpoints.   For mWOCF imputed data, 
subjects who withdraw from the trial early due to an AE will have their missing data imputed 
using WOCF; all other missing data will be imputed using the last observation carried 
forward (LOCF).    
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 
Study center will be included as an effect in the efficacy analyses.  If necessary, study centers 
may be pooled prior to analyses.  This pooling will take place and be documented prior to 
unblinding.   
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 18.0) system for reporting (preferred term and body 
system). 
Prior and Concomitant medications will be coded using WHO-DD (Drug Dictionary) 
(Version June 2015). 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                       
CONFIDENTIAL 
 
P a g e  | 16 
 
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. 
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 2. 
Figure 2 
SDTM, ADaM, and TFL Development and Validation 
 
Where: 
1. Development, Validation, and Maintenance of SDTM Domains 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                       
CONFIDENTIAL 
 
P a g e  | 17 
 
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. 
 
7.4. 
Planned Study Analyses 
7.4.1. 
Statistical Summaries: Descriptive and Inferential 
All statistical tests will be two-sided and a difference resulting in a p-value of less than or 
equal to 0.05 will be considered statistically significant.  All p-values will be rounded to and 
displayed in four decimals.  If a p-value less than 0.0001 occurs it will be shown in tables as 
<0.0001. 
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 by treatment.  For categorical variables, the 
counts and proportions of each value will be tabulated by treatment.  Expansion of 
descriptive table categories within each treatment 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. 
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. The Data Safety Monitoring Board 
(DSMB) may request safety information at its discretion at any time during the study.  
Further details of the DSMB can be found in the DSMB Charter. 
7.5. 
Multiple Testing Procedures 
The AERT 40 mg dose will be compared with placebo first (for both TNmAS-MAL and 
CGIC).  If both comparisons are significant (showing superiority) at the 0.05 level then the 
AERT 80 mg dose will be tested at the 0.05 level (both TNmAS-MAL and CGIC).  Both co-
primary efficacy endpoints need to meet the 0.05 level for the AERT 40 mg dose comparison 
with placebo for the study to be considered a success.  Therefore, no adjustment for 
multiplicity is needed.  No other adjustments for multiplicity will be implemented. 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                       
CONFIDENTIAL 
 
P a g e  | 18 
 
8. 
SUMMARY OF STUDY DATA 
8.1. 
Subject Disposition 
A summary of the analysis sets includes the number and percentage of subjects in each 
treatment group for the following categories: subjects screened, subjects randomized, 
subjects in the safety population, subjects in the ITT population, subjects in the mITT 
population, and subjects in the PP population. All percentages will be based on the number of 
subjects randomized.  
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 
randomized. 
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 
Major protocol violations, as determined by a Sponsor blinded review of the data prior to 
database lock and unblinding of the study, may result in the removal of a subject’s data from 
the PP population. The Sponsor or designee will be responsible for producing the final 
violation file; this file will include a description of the protocol violation and clearly identify 
whether or not this violation warrants exclusion from the PP population. This file will be 
finalized prior to database lock, and all information will be included in the SDTM.DV 
domain (deviations domain). 
All protocol violations will be presented in a data listing, with a flag to indicate if a violation 
was considered major and resulted in the exclusion of the subject from the PP population. A 
summary table will 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 by treatment group and overall.  The demographic data and baseline 
characteristics will be summarized for the safety, ITT, mITT, and PP populations. 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 18.0. 
Subject medical and surgical history data including specific details will be presented in a 
listing. 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                       
CONFIDENTIAL 
 
P a g e  | 19 
 
8.5. 
Prior and Concurrent Medications 
The number and percentages of all concomitant medications will be summarized by 
treatment group, 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 by treatment group. All summaries will be 
performed using the safety population. 
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.  
8.6. 
Treatment Compliance 
Dosing information, including date of administration, will be listed by subject.  


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                       
CONFIDENTIAL 
 
P a g e  | 20 
 
9. 
EFFICACY ANALYSES 
9.1. 
Primary Efficacy 
9.1.1. 
Co-Primary Efficacy Endpoints 
The co-primary efficacy endpoints include the following: 
• Total Numeric-Transformed Modified Ashworth Score – Most Affected Limb 
(TNmAS - MAL) 
• Clinical Global Impression of Change (CGIC) 
9.1.2. 
Co-Primary Efficacy Analyses 
The AERT 40 mg dose will be compared with placebo first (for both TNmAS-MAL and 
CGIC).  If both comparisons are significant at the 0.05 level then the AERT 80 mg dose will 
be tested at the 0.05 level (both TNmAS-MAL and CGIC).  Both co-primary efficacy 
endpoints need to meet the 0.05 level for the AERT 40 mg dose comparison with placebo for 
the study to be considered a success.  Therefore, no adjustment for multiplicity is needed.  
The Day 84 comparison is the primary time point for both co-primary endpoints. 
Descriptive statistics for each co-primary efficacy variable will be tabulated by study visit 
and treatment group.  CGIC categories will also be summarized by frequencies and 
percentages by study visit and treatment group. 
Note that if two or more limbs tie for Most Affected at baseline, then the Visit 5 (Day 84) 
scores for the tied limbs are assessed and the one with the worst score at Visit 5 becomes the 
Most Affected Limb in the primary analysis. In the case of a tie at baseline and at Visit 5, 
then both scores from Visit 4 and Visit 5 are summed for each limb and the highest (worst) 
total is flagged as the Most Affected Limb. 
TNmAS-MAL will be analyzed using a restricted maximum likelihood (REML)-based mixed 
model for repeated measures (MMRM) with fixed effects for treatment, visit, study center, 
and the treatment-by-visit interaction; and with baseline score as a covariate.  The outcome 
variable will be change from baseline scores.  Study visit will be included in the model as a 
categorical variable (Visit 4 [Day 42] and Visit 5 [Day 84]) along with the treatment-by-visit 
interaction.  Least squares means (LS means) will be used to compare treatments. 
CGIC will also be analyzed using an REML-based MMRM with fixed effects for treatment, 
visit, study center, and the treatment-by-visit interaction.  As the CGIC is a change score, no 
value is measured at baseline.  The outcome variable will be CGIC scores.  Study visit will 
be included in the model as a categorical variable (Visit 4 [Day 42] and Visit 5 [Day 84]) 
along with the treatment-by-visit interaction.  LS means will be used to compare treatments. 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                       
CONFIDENTIAL 
 
P a g e  | 21 
 
For both models, pairwise treatment comparisons between the two AERT doses and placebo 
will be performed at each visit; however, the primary comparisons will be the contrasts 
between AERT 40 mg and placebo at Day 84.  Unstructured covariance matrices will be 
utilized.  If the model fails to converge with an unstructured covariance matrix other 
structures will be tried and the structure with the lowest corrected Akaike information 
criterion (AICC) will be used for the analysis.  Full details will be included in the CSR.  The 
Kenward Roger method will be used for computing the denominator degrees of freedom for 
the tests of fixed effects.  Study centers may be pooled prior to unblinding.   
9.1.3. 
Co-Primary Efficacy Sensitivity Analyses 
A number of sensitivity analyses will be performed to assess the robustness of the results of 
the primary analyses and to test the assumptions of the MMRM model.  Details of statistical 
methods for these sensitivity analyses are described below: 
• The primary efficacy analyses will be repeated using the mITT and PP populations. 
• Separate models including a treatment-by-study center effect will be utilized to assess 
if treatment effects differ by study center.  If the treatment-by-study center interaction 
term is significant in either model the co-primary efficacy results will be summarized 
descriptively by study center (possibly pooled). 
• Using the primary efficacy MMRMs, the average of Days 42 and 84 will be 
compared between treatments using linear contrasts for both co-primary efficacy 
endpoints.   
• To determine if the primary efficacy results are affected by subjects who withdraw 
early from the trial, the TNmAS-MAL and CGIC scores for subjects who withdraw 
from the trial early will be compared graphically with the scores for subjects who 
completed the trial.  The last observed TNmAS-MAL and CGIC score captured prior 
to early termination will be plotted and compared against the average TNmAS-MAL 
and CGIC scores calculated from subjects who complete the trial.  This type of plot 
will illustrate if subjects who dropout early from the study are performing better or 
worse than those subjects who complete the study.   
• To ensure that subjects who withdraw early from the trial with “good” TNmAS-MAL 
and CGIC scores do not unduly bias the results of the primary efficacy analyses in a 
positive direction, subjects who withdraw early from the trial will be penalized.  In 
this analysis, subjects will be penalized for withdrawing early from the trial with a 
“good” TNmAS-MAL or CGIC score.  Subjects who withdraw early from the trial 
will be penalized more. 
The procedure used to penalize these subjects for TNmAS-MAL follows.  First, 
determine the median TNmAS-MAL change from baseline score using only scores 
less than 0 (indicating improvement) within treatment group at each visit. Note that 
subjects whose scores are greater than or equal to 0 are not used when calculating the 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                       
CONFIDENTIAL 
 
P a g e  | 22 
 
median. For any subject that discontinues for any reason, check to see if his or her 
TNmAS-MAL change from baseline score for the current visit is less than the median 
for the current visit described above (do this for every visit for which the subject has a 
score available). If the early termination visit falls between two scheduled visits, the 
medians calculated from the scheduled visits will be interpolated to the termination 
time.  If the subject’s score is less than the median at that visit, then scale the 
subject’s current score by multiplying it by the subject’s last week that the TNmAS-
MAL score is observed divided by 12.  For example, if a subject discontinues and has 
the final TNmAS-MAL score at Week 7, then anytime the subject has a score less 
than the respective within treatment/visit median described above, that score will be 
multiplied by 7/12. These new scores are then used in the primary efficacy MMRM 
model. 
A similar approach will be used for CGIC.  CGIC values of 1 (very much improved), 
2 (much improved), or 3 (improved) will be utilized to determine the median. 
• The impact of missing data will be determined in an analysis using an analysis of 
covariance (ANCOVA) model based on multiple worst observation carried forward 
(mWOCF) imputed data.  For mWOCF imputed data, subjects who withdraw from 
the trial early due to an AE will have their missing data imputed using WOCF; all 
other missing data will be imputed using the last observation carried forward (LOCF).  
The models will include treatment and study site as fixed effects.  The model for 
TNmAS will also include baseline score as a covariate. 
• The primary efficacy analysis model (MMRM) makes the assumption that missing 
data are “missing at random” (MAR).  When data are MAR, the missingness of the 
data does not depend on the missing value after conditioning on the observed data 
(i.e., prior assessments and baseline covariates). Note that when the missingness of 
the data depends on the values of the missing variables after conditioning on the 
observed data, the data are called “missing not at random” (MNAR).  In order to 
assess the MAR assumption, a placebo-based pattern mixture model (PMM) will be 
utilized following the steps outlined in Ratitch B and O’Kelly, M.J. (2011) for both 
TNmAS-MAL and CGIC.   
Briefly, the strategy for implementing this approach is as follows for subjects with 
missing data: 
1. Impute all non-monotone (intermittent) missing data using the MCMC 
method of PROC MI.  Note that this imputation will sample data within each 
treatment group.  SAS pseudo code is provided below.  


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                       
CONFIDENTIAL 
 
P a g e  | 23 
 
2. Using the imputed datasets from Step #1 that are now mononotone missing 
(no intermittent missing data), a single call to PROC MI (including the 
MNAR statement) will be utilized to impute the monotone missing data.  
Additional details are provided below. 
 Within the call to PROC MI, one timepoint is imputed at a time.  Day 
42 first, then Day 84. 
 When imputing at time-point t, the imputation step will include all 
placebo subjects, but only those from the active arms that have a value 
missing at time-point t. Subjects with non-missing data that are on 
active arms will not contribute to the estimation for this step. 
 Repeat the above step for all timepoints t. Thus, the data for timepoint 
t+1 (Day 84) uses the data imputed from previous timepoints (Day 
42). 
SAS pseudo code is provided below.  SAS accomplishes this iterative process 
in one step.  Note that the treatment level 3 is the placebo treatment group: 
 
3. When all missing data are imputed, the MMRM models, as described in 
Section 9.1.2, will be used to analyze the TNmAS-MAL and CGIC endpoints.  
PROC MIANALYZE will be used to combine the parameters from the 
analyses for inference. 
• The above PMM and MMRM analyses will be repeated using only two arms (Placebo 
and AERT 40 mg). The overall treatment effect could be diluted by the AERT 80 mg 
dose if there a significant number of discontinuations at this dose level compared to 
the AERT 40 mg dose, and these analyses serve to compare to Placebo without that 
possibility. Additionally, this analysis will be completed on Placebo and AERT 80 
mg arms, in the unlikely event that there is a trend in the lower dose level causing 
discontinuations. 
9.2. 
Secondary Efficacy 
9.2.1. 
Secondary Efficacy Endpoints 
 
The secondary efficacy endpoints include the following: 
• Patient Global Impression of Change (PGIC) 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                       
CONFIDENTIAL 
 
P a g e  | 24 
 
• EDSS 
• TNmAS – Total Limbs (TL) 
9.2.2. 
Secondary Efficacy Analyses 
Secondary efficacy endpoints will be summarized descriptively and analyzed using the same 
type of MMRM analysis used for the co-primary efficacy endpoints.  PGIC will follow the 
same MMRM that is used for CGIC.  EDSS and TNmAS-TL will follow the same MMRM 
that is used for TNmAS-MAL.  Pairwise comparisons between the AERT doses and placebo 
will be provided at each visit where data are collected.  Additional factors (e.g., baseline 
renal function) along with interaction terms may be included in the models as sensitivity 
analyses. 
 
10. 
SAFETY ANALYSES 
All Safety analyses will be conducted using the Safety population.  All safety analyses will 
be completed using the actual treatment a subject received (i.e. “as Treated”). 
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 18.0) for each 
treatment group.  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. 
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 30 days after the 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.  


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                       
CONFIDENTIAL 
 
P a g e  | 25 
 
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, for each treatment group.  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 for each treatment 
group.  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. 
10.3. 
Clinical Laboratory Evaluations 
Clinical Laboratory results will be summarized descriptively for each treatment group 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 for each treatment group 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.  


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                       
CONFIDENTIAL 
 
P a g e  | 26 
 
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 for each treatment group 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 for each treatment group 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 
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 


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                       
CONFIDENTIAL 
 
P a g e  | 27 
 
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 
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).  
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-


Osmotica Pharmaceutical 
                         CLN.OS440-3004.SAP.02 
Study OS440-3004 Statistical Analysis Plan                                                                       
CONFIDENTIAL 
 
P a g e  | 28 
 
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. 
 
12 
REFERENCES 
Ratitich, B. and O’Kelly, M.J. (2011). Implementation of Pattern-Mixture Models Using 
Standard SAS / STAT Procedures.