Clinical trial NCT03679975
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: Aquestive Therapeutics
Start date: 2018-04-04; Completion date: 2018-12-21
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective is to evaluate the effect, if any, of a single 50 mg dose of Riluzole Oral Soluble Film (ROSF) on swallowing safety in individuals with amyotrophic lateral sclerosis.

Detailed description:
This was a single site, single dose, open-label study with one group of male or female patients between 18-80 years old with a diagnosis of Probable or Definite Amyotrophic Lateral Sclerosis (ALS) according to revised El-Escorial Criteria. Patients seen in the ALS Clinic at the University of Florida were screened to determine eligibility for participation in the study according to the specified inclusion/exclusion criteria. Following informed consent and enrollment, subjects were given a complete physical and neurological examination including the validated Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). Swallowing safety was assessed using the gold standard Videofluoroscopic Swallowing Study (VFSS) to allow direct visualization of the swallowing process and any episodes of penetration or aspiration were quantified using the validated Penetration Aspiration Scale (PAS). Subjects participated in a standardized protocol that includes 11 bolus stimuli presentations of different liquid and food materials to test swallowing function using a progression of textures and materials. Immediately following this assessment, subjects were given a single dose of ROSF 50 mg, placed on the median lingual sulcus of the dorsum of the tongue (area under the tongue on the midline groove that separates the surface of the tongue into right and left halves). Three minutes after the administration of ROSF, the identical standardized VFSS protocol was re-administered to allow a comparison of swallowing safety (using the PAS scale) pre- versus post-ROSF administration.

The original plan was to enroll 30 patients for a final sample size of 25 completed patients. The protocol stipulated that, depending upon the study enrollment rate, the Sponsor could elect to perform an interim analysis using available data from the subset of subjects who had completed the study at that time. An interim assessment of the data was performed after 8 subjects had completed the study and a ninth patient had been screened and was awaiting VFSS. With agreement from the FDA, the Sponsor decided to terminate the study after 9 completed patients, based on the analysis of the first 8 completed patients showing no evidence of a harmful effect of one dose of ROSF 50 mg on swallowing function.

Arms: arm 1: Subjects with a diagnosis of probable or definite ALS in accordance with the Revised El-Escorial Criteria were administered a single dose of the Riluzole Oral Soluble Film (ROSF) 50 mg.
Interventions: intervention 1: Riluzole Oral Soluble film (ROSF) 50 mg
Intervention descriptions: intervention 1: Enrolled subjects underwent an instrumental evaluation of swallowing safety before and after administration of a single dose of the ROSF formulation containing 50 mg of riluzole.

Protocol documents:
Prot_000.pdf: 
NCT03679975
A Single Center Study to Evaluate the Effect of Riluzole Oral Soluble Film on Swallowing Safety 
in Individuals With Amyotrophic Lateral Sclerosis
Protocol 
18-Oct-2017


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly 
prohibited without written consent from MonoSol Rx LLC. 
Page 1 of 55 
 
 
A Single Center Study to Evaluate the Effect of Riluzole Oral Soluble Film on 
Swallowing Safety in Individuals With Amyotrophic Lateral Sclerosis 
 
Amendment 1 
Summary of Changes from Version 1.0 (July 27, 2017) to Version 2.0 (October 18, 2017)  
 
 
Note:  
 
Major changes described in the following table have been made in this document to address 
the following issues: 
• Additional exclusion added to clarify the exclusion for the PAS score applies to 
any previous swallowing studies 
• Additional exclusion added for subjects with a history of two or more episodes of 
aspiration pneumonia requiring hospitalization 
• Modified hepatic function exclusion requirement for subjects currently on 
Riluzole 
• Modified hepatic function exclusion requirement for subjects receiving Riluzole 
for the first time 
• Added description of comprehensive and brief physical examinations and 
comprehensive neurological and brief neurological examinations 
 
 
Few minor changes involving wordsmithing for clarity and consistency, punctuation, and 
correction of typos have also been made but are not included in this table because they are 
not substantive changes. However, they are visible in the tracked-changes version of the 
protocol 
 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly 
prohibited without written consent from MonoSol Rx LLC. 
Page 2 of 55 
 
 
Section 
Version No 1.0  July 
27, 2017 
Amendment 1 (Version 2.0) 
October 18, 2017 
Rationale 
3. Synopsis 
– 
Exclusion 
Criteria 
  
 
p 7 
2. Subjects with a prior 
swallowing study that has 
shown a PAS of 3 or greater 
3. Subjects with a history of 
two or more episodes of 
aspiration pneumonia 
requiring hospitalization 
 
 
Additional exclusions added 
in response to Information 
Request (IR)  - IND 
130939-Comments on new 
protocol 
submission/SN0003_24_Au
gust_2017 
 3. 
Synopsis – 
Exclusion 
Criteria 
p 7 
8. 
Subjects with 
hepatic impairment 
as defined by 
baseline elevations 
of serum 
aminotransferases 
greater than 5 
times upper limit of 
normal or  
evidence of liver 
dysfunction (e.g., 
elevated bilirubin ). 
p 7 
10. 
Subjects currently 
taking riluzole with ALT 
levels greater than 5 times 
upper limit of normal or with 
evidence of clinical jaundice.  
(Riluzole should be 
discontinued in these 
patients). 
 
 
 
Changed to be consistent 
with the Reference Listed 
Drug (RLD), RILUTEK 
(NDA 020599) label 
3. Synopsis 
– 
Exclusion 
Criteria 
 
P 7 
11. Subjects who will be 
receiving riluzole for the first 
time who exhibit baseline 
elevations of several LFTs 
(especially elevated bilirubin).  
(These findings at baseline 
should preclude the use of 
riluzole including ROSF.). 
Added to be consistent with 
the Reference Listed Drug 
(RLD), RILUTEK (NDA 
020599) label 
8.1.2 
Exclusion 
 
p 18 
2. Subjects with a prior 
Additional exclusions added 
in response to Information 
Request (IR)  - IND 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly 
prohibited without written consent from MonoSol Rx LLC. 
Page 3 of 55 
 
 
Section 
Version No 1.0  July 
27, 2017 
Amendment 1 (Version 2.0) 
October 18, 2017 
Rationale 
Criteria  
swallowing study that has 
shown a PAS of 3 or greater 
3. Subjects with a history of 
two or more episodes of 
aspiration pneumonia 
requiring hospitalization 
 
130939-Comments on new 
protocol 
submission/SN0003_24_Au
gust_2017 
8.1.2 
Exclusion 
Criteria 
P 19 
8. 
Subjects with 
hepatic impairment 
as defined by 
baseline elevations of 
serum 
aminotransferases 
greater than 5 times 
upper limit of normal 
or  evidence of liver 
dysfunction (e.g., 
elevated bilirubin ). 
P 19 
10.. 
Subjects currently 
taking riluzole with ALT 
levels greater than 5 times 
upper limit of normal or with 
evidence of clinical jaundice.  
(Riluzole should be 
discontinued in these patients 
.) 
 
Changed to be consistent 
with the Reference Listed 
Drug (RLD), RILUTEK 
(NDA 020599) label 
8.1.2 
Exclusion 
Criteria 
 
P 19 
11. Subjects who will be 
receiving riluzole for the first 
time who exhibit baseline 
elevations of several LFTs 
(especially elevated bilirubin).  
(These findings at baseline 
should preclude the use of 
riluzole including ROSF.). 
Added to be consistent with 
the Reference Listed Drug 
(RLD), RILUTEK (NDA 
020599) label 
10.2.2.1.   
Videofluor
oscopy 
Swallow 
Study 
(VFSS 1-
PAS) 
 
P 27  
The start time and finish time 
for the standardized bolus 
protocol will be recorded for 
both VFSS 1 and VFSS 2. 
Added in response to 
Information Request (IR)  - 
IND 130939-Comments on 
new protocol 
submission/SN0003_24_Au
gust_2017 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly 
prohibited without written consent from MonoSol Rx LLC. 
Page 4 of 55 
 
 
Section 
Version No 1.0  July 
27, 2017 
Amendment 1 (Version 2.0) 
October 18, 2017 
Rationale 
10.2.2.1.   
Videofluor
oscopy 
Swallow 
Study 
(VFSS 1-
PAS) 
P 26  
Immediately 
following VFSS 1-
PAS, the patient will 
then be administered 
ROSF on the dorsum 
of tongue along the 
median lingual 
sulcus. 
P 28  
…sulcus, , and the time of 
administration will be 
recorded. 
Added in response to 
Information Request (IR)  - 
IND 130939-Comments on 
new protocol 
submission/SN0003_24_Au
gust_2017 
10.2.2.1.   
Videofluor
oscopy 
Swallow 
Study 
(VFSS 1-
PAS) 
 
P 28 
The investigator should 
record whether or not ROSF 
is fully dissolved at 3 minutes 
after dosing. In the event that 
ROSF is not fully dissolved at 
3 minutes, the investigator 
will record the time that it is 
confirmed that ROSF is fully 
dissolved. 
Added in response to 
Information Request (IR)  - 
IND 130939-Comments on 
new protocol 
submission/SN0003_24_Au
gust_2017 
10.3.6.
 
Clin
ical 
Assessment
s 
 
P 30 
Subjects will undergo a 
comprehensive physical and 
neurological examination at 
screening, and a brief physical 
and neurological examination 
at Visit 1 following the 
second VFSS.   
The comprehensive physical 
examination will include 
complete vital signs, weight, 
height, general appearance, 
and evaluation of systems: 
head, ears, eyes, nose, and 
throat; respiratory; abdomen; 
lymph nodes; spine; skin; 
cardiovascular; and 
The CRO managing the 
protocol requested  a 
description of the 
comprehensive and  the 
brief physical exam and the 
neurological exam and brief 
neurological exam 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly 
prohibited without written consent from MonoSol Rx LLC. 
Page 5 of 55 
 
 
Section 
Version No 1.0  July 
27, 2017 
Amendment 1 (Version 2.0) 
October 18, 2017 
Rationale 
extremities.  The brief general 
physical examination will 
include abbreviated vital signs 
(blood pressure, heart rate, 
respiratory rate), and 
examination of the 
cardiovascular and respiratory 
systems and abdomen. Other 
elements may be included 
depending on symptoms or 
physical findings. 
The comprehensive 
neurological examination will 
include (as permitted by the 
patient’s capabilities) cranial 
nerves 2-12, muscle tone and 
strength, tendon reflexes and 
plantar response, sensory 
function (pain, light touch, 
position, vibration), 
coordination (finger-nose), 
and gait.  The brief 
neurological examination will 
include cranial nerves 2-12, 
muscle strength, tendon 
reflexes, plantar response, and 
sensory function (pain, light 
touch, position, vibration).  
Other elements may be 
included depending on 
symptoms or physical 
findings 
10.3.12.
 
Phy
sical and 
Neurologic
al 
Examinatio
 
P 34 
Subjects will undergo a 
comprehensive physical and 
neurological examination at 
screening, and a brief physical 
The CRO managing the 
protocol requested  a 
description of the 
comprehensive and  the 
brief physical exam and the 
neurological exam and brief 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly 
prohibited without written consent from MonoSol Rx LLC. 
Page 6 of 55 
 
 
Section 
Version No 1.0  July 
27, 2017 
Amendment 1 (Version 2.0) 
October 18, 2017 
Rationale 
n 
and neurological examination 
at Visit 1 following the 
second VFSS.   
The comprehensive physical 
examination will include 
complete vital signs, weight, 
height, general appearance, 
and evaluation of systems: 
head, ears, eyes, nose, and 
throat; respiratory; abdomen; 
lymph nodes; spine; skin; 
cardiovascular; and 
extremities.  The brief general 
physical examination will 
include abbreviated vital signs 
(blood pressure, heart rate, 
respiratory rate), and 
examination of the 
cardiovascular and respiratory 
systems and abdomen. Other 
elements may be included 
depending on symptoms or 
physical findings. 
The comprehensive 
neurological examination will 
include (as permitted by the 
patient’s capabilities) cranial 
nerves 2-12, muscle tone and 
strength, tendon reflexes and 
plantar response, sensory 
function (pain, light touch, 
position, vibration), 
coordination (finger-nose), 
and gait.  The brief 
neurological examination will 
include cranial nerves 2-12, 
muscle strength, tendon 
reflexes, plantar response, and 
neurological exam 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly 
prohibited without written consent from MonoSol Rx LLC. 
Page 7 of 55 
 
 
Section 
Version No 1.0  July 
27, 2017 
Amendment 1 (Version 2.0) 
October 18, 2017 
Rationale 
sensory function (pain, light 
touch, position, vibration).  
Other elements may be 
included depending on 
symptoms or physical 
findings. 
 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly 
prohibited without written consent from MonoSol Rx LLC. 
Page 8 of 55 
 
 
 
FULL STUDY TITLE 
 
A Single Center Study to Evaluate the Effect of Riluzole Oral Soluble Film on Swallowing 
Safety in Individuals With Amyotrophic Lateral Sclerosis  
 
 
SHORT STUDY TITLE 
 
Riluzole Oral Soluble Film Swallowing Safety in Amyotrophic Lateral Sclerosis 
 
 
Protocol Number: 17MO1R-0012 
 
Protocol Version Number: Amendment 1, V2.0 
Protocol Version Date: October 18, 2017 
 
Sponsor: 
MonoSol Rx, LLC 
30 Technology Drive 
Warren, NJ 07059 
USA 
 
Phase 2 
 
IND Number: 130939 
 
Confidentiality Statement 
The information contained herein is confidential and proprietary in nature, and will not be disclosed 
to any third party without written approval of authorized designee. This document may be disclosed 
to the appropriate institutional review boards or to duly authorized representatives of the US Food and 
Drug Administration or a national regulatory authority under the condition that they maintain 
confidentiality. 




Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly 
prohibited without written consent from MonoSol Rx LLC. 
Page 10 of 55 
 
 
 
2. 
INVESTIGATORS AND FACILITIES 
Principal Investigators 
Emily Plowman, PhD, CCC-SLP 
Department of Speech, Language, and Hearing Sciences 
College of Public Health and Health Professions 
University of Florida 
Gainesville, Florida 32610 
Email:  eplowman@phhp.ufl.edu 
 
James Wymer, MD, PhD 
Department of Neurology, College of Medicine 
University of Florida 
Gainesville, Florida 32610 
Email: james.wymer@neurology.ufl.edu 
Sponsor: 
Rikin Mehta 
MonoSol Rx, LLC 
30 Technology Drive 
Warren, NJ, 07059 
Tel: 908-941-1753; Fax: 908-561-1209 
Clinical Research Organization: 
inVentiv Health 
202 Carnegie Center 
Princeton, NJ 08540 USA 
Tel.: 1-609-951-6800 
Clinical Laboratory: 
Covance Central Laboratory Services 
8211 Scicor Drive 
Indianapolis, IN 46214 USA 
Telephone: 888-268-2623 or 317-271-1200 
Statistical Facility: 
inVentiv Health 
202 Carnegie Center 
Princeton, NJ 08540 USA 
Tel.: 1-609-951-6800 
CRO Safety (Pharmacovigilance) 
Reporting: 
inVentiv Health Global Safety & Pharmacovigilance 
Facsimile: 1-866-856-1649 
Telephone Hotline No.: +1-888-750-8020 
E-mail: saereceipt.international@inventivhealth.com 
 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly 
prohibited without written consent from MonoSol Rx LLC. 
Page 11 of 55 
 
 
 
3. 
SYNOPSIS 
Title 
A single center study to evaluate the effect of Riluzole Oral Soluble Film 
(ROSF) on swallowing safety in individuals with amyotrophic lateral 
sclerosis.  
Objectives 
The primary objective is to evaluate the effect, if any, of a single 50 mg dose 
of Riluzole Oral Soluble Film (ROSF) on swallowing safety in individuals 
with amyotrophic lateral sclerosis. 
Experimental 
Design  
This is a single site, single dose, open-label safety study. Approximately 
thirty (30) individuals with amyotrophic lateral sclerosis (ALS) will be 
enrolled.  Subjects seen in the ALS Clinic at the University of Florida will be 
screened to determine eligibility according to the specified 
inclusion/exclusion criteria. Following enrollment and informed consent, 
subjects will undergo a clinical evaluation including the validated 
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-
R). Swallowing safety will be assessed using the gold standard 
Videofluoroscopic Swallowing Study to afford direct visualization of the 
swallowing process and any episodes of penetration or aspiration quantified 
using the validated Penetration Aspiration Scale (PAS). Subjects will 
undergo a standardized protocol that includes 12 bolus stimuli presentations 
of different liquid and food materials to test the swallow across a continuum 
of textures and materials. Immediately following, subjects will be given a 
single dose of riluzole oral soluble film (ROSF) 50mg, placed on the median 
lingual sulcus of the dorsum of the tongue. Three minutes after the 
administration of ROSF, the identical standardized VFSS protocol will be re-
administered to allow a comparison of swallowing safety (using the PAS 
scale) pre vs. post ROSF administration. 
Interventions  ROSF is a new formulation of riluzole 50mg that allows for rapid dissolution 
of the medication through a soluble film placed on the dorsum of the tongue 
along the median lingual sulcus.  
Study 
Duration 
 
Participant 
Duration: 
The anticipated time from study enrollment until completion of data analyses 
is approximately 9 months. 
Total study participant time is expected to be approximately 30 days from 
time of screening to completion of study. 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly 
prohibited without written consent from MonoSol Rx LLC. 
Page 12 of 55 
 
 
Study 
Population 
and Sample 
Size 
Approximately 30 subjects with ALS will be enrolled. The inclusion criteria 
are intended to provide a representative cohort of subjects with ALS who are 
currently on an oral diet and able to take foods and liquids by mouth, 
equivalent to a score of 3 or above on the Functional Oral Intake Scale 
(Crary, 2005). Inclusion will require a diagnosis of probable or definite ALS 
in accordance with the Revisited El-Escorial Criteria (Cedarbaum, 1999), a 
prescription to take riluzole at or before the time of the administration of 
study drug, no allergies or contraindications to barium, riluzole or inactive 
ingredients* in ROSF, and no contraindications to study procedures. Female 
subjects must not be pregnant or breast-feeding.  
*See Investigator’s Brochure  
Phase 
2 
Test Drug 
 
Riluzole Oral Soluble Film 50 mg (MonoSol Rx, LLC) 
 
Inclusion 
Criteria 
1. Male or female subjects between 18-80 years of age, 
inclusive 
2. Subjects have a diagnosis of probable or definite ALS 
in accordance with the Revisited El-Escorial Criteria 
(Cedarbaum, 1999) 
3. Subjects must be currently on an oral diet and able to 
take foods and liquids by mouth equivalent to a score 
of 3 or above on the Functional Oral Intake Scale 
(Crary, 2005).  
4. Subjects must have no known allergy to barium 
sulfate, riluzole or inactive ingredients* in ROSF. 
5. Subjects or subject’s legally authorized representative 
must be willing and able to complete informed 
consent/assent and HIPAA authorization.  
6. Ability to comprehend and be informed of the nature 
of the study, as assessed by the PI or Sub-Investigator. 
7. Subjects prescribed to take riluzole at or before the 
time of first dosing. (The study is open to subjects 
currently taking riluzole at screening, subjects who are 
not currently taking riluzole at screening who have 
taken riluzole in the past, and subjects to be newly 
started on riluzole (given as ROSF in the course of 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly 
prohibited without written consent from MonoSol Rx LLC. 
Page 13 of 55 
 
 
this study).  
8. Availability to volunteer for the entire study duration 
and willing to adhere to all protocol requirements 
9. Female subjects of childbearing potential must have a 
negative urine pregnancy test at Screening and Visit 1.  
Female subjects of childbearing potential (i.e. not 
surgically sterile, not 2 years postmenopausal, or not 
with a sterile partner) must have a negative pregnancy 
test at screening and Visit 1, agree to abstinence, 
practicing double barrier contraception or using an 
FDA approved barrier method contraceptive (e.g., 
licensed hormonal or barrier methods) for greater than 
2 months prior to screening visit and commit to an 
acceptable form of birth control for the duration of the 
study and for 30 days after participation in the study. 
*See Investigator Brochure  
Exclusion 
Criteria 
1. Subjects who score 2 or below on the Functional Oral Intake 
Scale  (Crary, 2005) 
2. Subjects with a prior swallowing study that has shown a PAS 
of 3 or greater 
3. Subjects with a history of two or more episodes of aspiration 
pneumonia requiring hospitalization 
4. Subjects with a history of clinically significant liver disease, 
renal disease, or any other medical condition judged to be 
exclusionary by the investigator 
5. Subjects who are unwilling to sign informed consent or 
subjects who for any other reason in the judgment of 
investigator are unable to  complete the study 
6. Female subjects who have a positive urine pregnancy test 
(βhCG) at screening or visit 1, are trying to become pregnant 
or are breastfeeding. 
7. Subjects with active cancer within the previous 2 years, 
except treated basal cell carcinoma of the skin 
8. Subjects who have taken any experimental drug within 30 
days prior to enrollment or within 5 half-lives of the 
investigational drug –whichever is the longer period.  


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly 
prohibited without written consent from MonoSol Rx LLC. 
Page 14 of 55 
 
 
However, subjects who have previously completed other 
MonoSol Rx sponsored ROSF clinical studies within the last 
30 days prior to enrollment may be eligible for consideration 
for entry into this study. 
9. Subjects with known history or presence of moderate or 
severe renal impairment as defined by a calculated creatinine 
clearance of ≤50 mL/minute 
10. Subjects currently taking riluzole with ALT levels greater 
than 5 times upper limit of normal or with evidence of clinical 
jaundice.  (Riluzole should be discontinued in these patients.)  
11.  Subjects who will be receiving riluzole for the first time who 
exhibit baseline elevations of several LFTs (especially 
elevated bilirubin). (These findings at baseline should 
preclude the use of Riluzole including ROSF). 
12. Use of potentially hepatotoxic drugs: (e.g., allopurinol, 
methyldopa, sulfasalazine). 
13. Subjects with clinically significant abnormal laboratory 
values in the judgment of the investigator 
14. Use of strong or moderate CYP1A2 inhibitors (e.g., 
ciprofloxacin, enoxacin, fluvoxamine, methoxsalen, 
mexiletine, thiabendazole, vemurafenib, zileuton) and 
CYP1A2 inducers (e.g. rifampin and barbiturates) in the 
previous 30 days before drug administration.   
15. Anything else that, in the opinion of the investigator, would 
place the subject at increased risk or preclude the subject’s 
full compliance with or completion of the study 
16. Employee or immediate relative of an employee of the 
investigator, MonoSol Rx LLC, any of its affiliates or 
partners, or inVentiv Health. 
 
 
 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly 
prohibited without written consent from MonoSol Rx LLC. 
Page 15 of 55 
 
 
Assessments 
 
 
 
 
 
 
 
 
 
• Comprehensive/brief physical exam 
• Comprehensive/brief neurologic exam 
• ALS Functional Rating Scale – Revised (ALSFRS-R 
scale) 
• Functional Oral Intake Scale (Crary, 2005).  
• Eating Assessment Tool -10 (Belafsky, 2008) 
• Videofluoroscopic swallowing study (VFSS) 
• Penetration Aspiration Scale (PAS) (Rosenbek, 1999) 
• Adverse events 
• Clinical laboratory evaluation(s) 
• Urine Pregnancy Test (females of childbearing 
potential) 
• Vital Signs, Height and Weight 
• Medical history 
• Concomitant medication 
• Inclusion/exclusion criteria 
 
Statistical Analysis  
 
Primary Outcome: 
The primary objective is to assess the effect of the ROSF formulation, if any, on swallowing 
safety in subjects with ALS. The null hypothesis is that there will be no difference between 
the PAS scores (i.e. swallowing safety) obtained before and after administration of the study 
medication. 
The PAS scores obtained in swallow tests during VFSS 1-PAS (before ROSF) and VFSS 2-
PAS (after ROSF) will be compared within each subject with the non-parametric Wilcoxon 
Signed-Rank Test.  Alpha will be set at 0.05, two-tailed.  Analysis across each swallowing 
trial will be performed, providing 12 bolus stimuli trials and approximately 35 swallows and 
PAS scores for each elicited swallow across testing within each participant (across various 
textures and swallowing complexities given that multiple swallows are typically elicited per 
bolus stimuli trial) to ensure a comprehensive exam across a variety of liquid volumes, 
textures and consistencies). 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly 
prohibited without written consent from MonoSol Rx LLC. 
Page 16 of 55 
 
 
Sample size was determined for a within-person design (repeated measures, same subjects in 
VFSS 1-PAS and VFSS 2-PAS) using G*Power Version 3.1.9.2, assuming a correlation = 
0.6 across the two measurements. A sample size of n=25 would be able to detect at least a 1.0 
point difference (two-tailed), effect size 0.6, in PAS scores from Test 1 and Test 2 with 80% 
power. It is anticipated that approximately 20% of recruited ALS subjects will grossly 
aspirate during VFSS 1-PAS and will not have a VFSS 2-PAS performed (for both safety 
reasons and also because Test 2 would not yield any useful data due to a ceiling effect). 
Therefore enrollment is planned for a total of 30 subjects to account for this potential. 
Depending on the study enrollment rate, the Sponsor may elect to perform an interim 
analysis using available data from the subset of subjects who have completed the study at 
that time.  The results of this interim analysis will be used only for internal planning and 
possibly for sharing with regulatory authorities. The results of the interim analysis will have 
absolutely no influence on the subsequent conduct of the study. 
 
The following safety information will be included as descriptive summaries: 
• Type, incidence, and severity of adverse events 
• Physical and neurological examinations 
• Vital signs (heart rate, blood pressure, rate, temperature), Height/Weight 
• Clinical laboratory evaluation(s); see Section 10.3.7 Laboratory Evaluations  
• Urine pregnancy test (females of childbearing potential) 
• ALS Functional Rating Scale – Revised (ALSFRS-R) (Cedarbaum, 1999) 
• Functional Oral Intake Scale – FOIS (Crary, 2005)  
• Eating Assessment Tool 10 – (EAT-10) (Belafsky, 2008) 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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4. 
LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
AE 
adverse event 
ALS 
amyotrophic lateral sclerosis 
ALSFRS-R 
ALS Functional Rating Scale-Revised 
CDE 
Common Data Elements 
CFR 
Code of Federal Regulations 
CMSU  
Clinical Materials Services Unit 
CRF 
case report form 
CS 
clinically significant 
DM 
data management 
EAT-10 
Eating Assessment Tool -10 
EDC 
electronic data capture 
FDA     
Food and Drug Administration 
FOIS 
Functional Oral Intake Scale 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization  
MedDRA 
Medical Dictionary for Regulatory Activities 
NINDS 
National Institute of Neurological Disorders and Stroke 
PAS 
Penetration Aspiration Scale 
ROSF 
Riluzole Oral Soluble Film 
SAE 
serious adverse event 
SOA  
schedule of activities 
VFSS 
Videofluoroscopic Swallowing Study 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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5. 
TABLE OF CONTENTS 
1. 
PROTOCOL APPROVAL SIGNATORY PAGE........................................................9 
2. 
INVESTIGATORS AND FACILITIES .....................................................................10 
3. 
SYNOPSIS .................................................................................................................11 
4. 
LIST OF ABBREVIATIONS.....................................................................................17 
5. 
TABLE OF CONTENTS ...........................................................................................18 
6. 
BACKGROUND AND PHARMACOKINETICS .....................................................21 
6.1. 
Rationale .....................................................................................................................21 
6.2. 
Mechanism of Action .................................................................................................21 
6.3. 
Pharmacokinetics ........................................................................................................22 
6.4. 
Safety ..........................................................................................................................23 
7. 
STUDY OBJECTIVES ..............................................................................................24 
7.1. 
Primary Objectives .....................................................................................................24 
8. 
SELECTION AND ENROLLMENT OF SUBJECTS...............................................25 
8.1. 
Inclusion Criteria and Exclusion Criteria ...................................................................25 
8.1.1. 
Inclusion Criteria: .......................................................................................................25 
8.1.2. 
Exclusion Criteria: ......................................................................................................25 
8.2. 
Subject Withdrawal ....................................................................................................27 
8.3. 
Study Enrollment Procedures .....................................................................................27 
8.3.1. 
Subject Recruitment and Retention ............................................................................28 
8.3.2. 
Screening Logs ...........................................................................................................28 
8.3.3. 
Randomization/Treatment Assignment ......................................................................28 
9. 
DRUG PRODUCT .....................................................................................................29 
9.1. 
Drug Information ........................................................................................................29 
9.2. 
Handling of Study Drug, Packaging and Labeling .....................................................29 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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9.3. 
Concomitant Interventions ..........................................................................................30 
9.3.1. 
Required Concomitant Medications/Interventions .....................................................30 
9.3.2. 
Prohibited Medications/Interventions .........................................................................30 
10. 
STUDY PROCEDURES ............................................................................................31 
10.1. 
Schedule of Activities .................................................................................................31 
10.2. 
Timing of Study Activities .........................................................................................32 
10.2.1. 
Screening procedures ..................................................................................................32 
10.2.2. 
On-Study/On-Intervention Evaluations/Procedures ...................................................33 
10.2.3. 
Study Medication/Intervention Discontinuation Evaluations/Procedures ..................35 
10.2.4. 
On Study/Off-Intervention Evaluations ......................................................................36 
10.2.5. 
Final On-Study Evaluations ........................................................................................36 
10.2.6. 
Off-Study Requirements .............................................................................................36 
10.2.7. 
Pregnancy ...................................................................................................................36 
10.3. 
SPECIAL INSTRUCTIONS AND DEFINITIONS OF EVALUATIONS ...............37 
10.3.1. 
Protocol Deviations ....................................................................................................37 
10.3.2. 
Documentation of Amyotrophic Lateral Sclerosis .....................................................37 
10.3.3. 
Medical History ..........................................................................................................37 
10.3.4. 
Treatment History .......................................................................................................37 
10.3.5. 
Concomitant Medications/Treatments ........................................................................37 
10.3.6. 
Clinical Assessments ..................................................................................................37 
10.3.7. 
Laboratory Evaluations ...............................................................................................39 
10.3.8. 
ALS Functional Rating Scale – Revised (ALSFRS-R) Questionnaire .......................40 
10.3.9. 
Eating Assessment Tool -10  (EAT-10) .....................................................................40 
10.3.10. 
Functional Oral Intake Scale (FOIS) ..........................................................................41 
10.3.11. 
Subject Adherence Assessments .................................................................................41 
11. 
SAFETY AND ADVERSE EVENTS ........................................................................41 
11.1. 
Adverse Experience Reporting and Follow Up ..........................................................42 


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11.2. 
Assessing Relationship to Study Drug .......................................................................42 
11.3. 
Procedures for Reporting Adverse Events ..................................................................43 
12. 
CRITERIA FOR INTERVENTION DISCONTINUATION .....................................45 
13. 
STATISTICAL CONSIDERATIONS .......................................................................45 
13.1. 
General Design Issues .................................................................................................45 
13.2. 
Outcomes ....................................................................................................................45 
13.2.1. 
Primary Outcome: .......................................................................................................45 
13.3. 
Sample Size and Accrual ............................................................................................45 
13.4. 
Data Monitoring ..........................................................................................................46 
13.5. 
Data Analyses .............................................................................................................46 
13.5.1. 
Penetration Aspiration Scale (PAS) ............................................................................46 
13.5.2. 
Statistical Analysis ......................................................................................................46 
13.5.3. 
Power ..........................................................................................................................47 
14. 
PROTOCOL AMENDMENTS AND STUDY TERMINATION .............................47 
15. 
ETHICAL CONSIDERATIONS................................................................................48 
15.1. 
Basic Principles ..........................................................................................................48 
15.2. 
Institutional Review Board Review and Informed Consent .......................................48 
15.3. 
Delegation of Investigator Tasks ................................................................................49 
15.4. 
Subject Confidentiality ...............................................................................................49 
16. 
REFERENCES ...........................................................................................................50 
APPENDIX A ................................................................................................................................52 
APPENDIX B ................................................................................................................................53 
APPENDIX C ................................................................................................................................54 
APPENDIX D ................................................................................................................................55 
 
 
 
 
 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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6. 
BACKGROUND AND PHARMACOKINETICS 
Riluzole Oral Soluble Film (ROSF) is being developed by MonoSol Rx as an alternative 
dosage form with an alternate route of administration for the existing FDA-approved riluzole 
product, Rilutek® tablets. The ROSF product contains the active ingredient riluzole 
incorporated into a polymer-based film matrix utilizing MonoSol Rx’s PharmFilm® 
technology. The inactive ingredient composition, the film dimensions, and the manufacturing 
process selected for this drug product are based on the information gained from the 
development of ROSF and other film products produced by MonoSol Rx (ZUPLENZ® 4 mg 
and 8 mg and SUBOXONE® 2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg, and 12 mg/3 mg). 
6.1. 
Rationale 
The proposed indication for ROSF is the treatment of patients with Amyotrophic Lateral 
Sclerosis (ALS), the same as for Rilutek® (riluzole) tablets (US Package Insert; revision 
04/2016). Clinical trials with Rilutek® tablets have shown that the time to tracheostomy or 
death was longer for ALS patients receiving Rilutek® compared to placebo, and there was an 
early increase in survival in patients receiving Rilutek® compared to placebo (Riviere 1998; 
Chen 2016; Watanabe 2015). 
Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disorder marked by the 
disruption of upper and lower motor neuron function. Riluzole is an FDA approved drug for 
treatment of the motor impairments of this disease and is taken by a sizable proportion of 
ALS patients. Given that dysphagia, or swallowing impairment, occurs in a reported 85% of 
ALS patients at some point during the disease progression, the ability to ingest riluzole 
medications can be compromised. Medications that can be easily administered orally without 
water may improve the quality of life of ALS patients and improve patient care. The riluzole 
oral soluble film may circumvent the potential inability of an ALS patient to swallow the 
tablet form of the medication, because the patient or caregiver need only to place the film on 
the tongue, where the active drug can immediately dissolve into the saliva and be ingested 
with intentional swallowing or during the normal reflex of swallowing, eliminating the need 
for swallowing a tablet with liquid or crushing it into soft food. (Appendix B) Absorption 
primarily occurs through the gastrointestinal tract after swallowing. 
Therefore, the ROSF product has the potential to improve care and decrease daily burden on 
patients and caregivers.  
6.2. 
Mechanism of Action 
The mechanism by which riluzole exerts its therapeutic effects in patients with ALS is 
unknown (Rilutek® tablets, US package insert; revision 04/2016). Riluzole decreases the 
release of glutamate, thereby suppressing excitotoxicity. As oxidative stress and 


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excitotoxicity are early events in ALS pathogenesis (Harikrishnareddy 2015), glutamate-
mediated excitotoxicity has been postulated to be central to ALS pathogenesis, with motor 
neuron degeneration mediated by corticomotoneuronal hyperexcitability through 
transsynaptic anterograde processes (Eisen, 1992). According to Vucic and colleagues (Vucic 
2013), because riluzole inhibits glutamatergic transmission, it may be expected that riluzole 
could exert modulating effects on the transcranial magnetic stimulation parameters of cortical 
excitability. Such a finding would then provide an objective measure of drug efficacy in 
ALS. However, the modulating effects of riluzole on cortical function in ALS have been 
varied. Specifically, while some studies have reported that riluzole partially normalizes 
cortical excitability (Desiato 1999; Stefan 2001), others have failed to establish any cortical 
modulating effects (Sommer 1999; Caramia 2000). In addition to direct anti-glutamatergic 
activity, riluzole appears to exert modulating effects on Na+ channel function (Cheah 2010). 
Given that increased Na+ channel conductance may contribute to neurodegeneration through 
Ca2+-mediated processes (Stys 2005, 2007), the Na+ channel blockade by riluzole may 
provide an additional neuroprotective mechanism in ALS. Of further relevance, riluzole may 
in part exert its anti-glutamatergic effects by inhibiting Na+ channel conductance and 
reducing glutamate release from presynaptic nerve terminals (Jimonet 1994; Cheah 2010).  
6.3. 
Pharmacokinetics 
According to the Rilutek® US package insert (revision 04/2016), riluzole is well absorbed 
with average absolute oral bioavailability of approximately 60% (CV=30%). Cmax occurred at 
approximately 1.0 hour to 1.5 hours after administration (Le Liboux 1997, 1999). AUC 
values were linearly related to dose over a dose range of 25 mg to 100 mg.  A high fat meal 
decreases absorption, reducing AUC by about 20% and peak blood levels by about 45%. The 
mean elimination half-life of riluzole is 12 hours (CV=35%) after repeated doses. With 
multiple-dose administration, riluzole accumulates in plasma by about twofold, and steady-
state is reached in less than 5 days. Riluzole is 96% bound to plasma proteins over the 
clinical concentration range, mainly to albumin and lipoproteins  
A human pilot bioavailability study (Study 1897) comparing ROSF 50mg with Rilutek® 
tablets 50mg found that the extent of absorption was approximately 14% greater and the rate 
of absorption was approximately 6% lower for the ROSF without water than for an intact 
Rilutek® tablet administered with 240 ml of water. When ROSF was administered with 
240ml of water, the extent of absorption was approximately 9% greater and the rate of 
absorption was approximately 12% lower than for the intact Rilutek® tablet administered 
with 240 ml of water. 
The pilot bioavailability study (Study 1897) was an open-label, randomized, single-dose, 
three-period, four-treatment, four-arm, incomplete crossover study. Sixteen adult, non-
smoking subjects were enrolled, and all provided data valid for pharmacokinetic analysis. 
The four treatments were A: ROSF 50 mg administered without water; B: ROSF 50 mg 
administered with 240 mL water; C: Rilutek® 50 mg intact tablet administered with 240 mL 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
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of water; and D: Rilutek® 50 mg tablet, crushed, and administered with 15 mL applesauce. 
The objective was to compare under fasting conditions the bioavailability of the ROSF 50mg 
administered with or without water to that of the intact Rilutek® 50 mg tablet, administered 
with 240 mL of water, i.e., treatments A and B compared with treatment C.  
For Treatment A (film without water) vs. Treatment C (intact tablet), Treatment A had 
approximate 14% higher extent of absorption of riluzole and an approximate 6% lower rate 
of the absorption of riluzole than Treatment C. The geometric mean T/R ratio for AUC0-t and 
Cmax was 113.70% with 90% CI 98.9-130.7%, and 94.36% with 90% CI 74.3-119.7%, 
respectively. For Treatment B (film with water) vs. Treatment C (intact tablet), Treatment B 
had approximate 9% higher extent of absorption of riluzole and an approximate 12% lower 
rate of the absorption of riluzole than Treatment C. The geometric mean T/R ratio for AUC0-t 
and Cmax was 108.6% with 90% CI 93.4-126.2%, and 88.1% with 90% CI 68.1-114.0 %, 
respectively. 
Of note, in the pilot bioavailability study (Study 1897), inter-subject variability for ROSF 
50mg without water for AUC0-t and AUC0-inf was reported as 25 and 26%, respectively, and 
for Cmax, 38%. In contrast, inter-subject variability for the Rilutek® 50mg administered with 
240 mL water for AUC0-t and AUC0-inf was reported as 39 and 40%, respectively, and for 
Cmax, about 48%. The apparent difference between formulations in inter-subject variability 
remained when this comparison was limited to the eight subjects in Study 1897 who received 
both treatments. Intra-subject variability in pilot bioavailability study (Study 1897) was 
reported as 18 and 19% for AUC0-t and AUC0-inf, respectively, and 32% for Cmax.  
6.4. 
Safety 
The most commonly observed AEs associated with the use of Rilutek® that occurred in at 
least 2% of patients (50mg twice daily) in pooled Clinical Study 1 and 2, and at a higher rate 
than placebo were asthenia, nausea, decreased lung function, hypertension, abdominal pain, 
vomiting arthralgia, dizziness, dry mouth, insomnia, pruritus, tachycardia, flatulence, 
increased cough, peripheral edema, urinary tract infection, circumoral paresthesia, 
somnolence, vertigo, eczema. Of those patients who discontinued due to adverse events, the 
most commonly reported were nausea, abdominal pain, constipation, and ALT elevations.  
The following adverse reactions have been identified during the postmarketing use of 
Rilutek®: Acute hepatitis and icteric toxic hepatitis and renal tubular impairment. 
Riluzole Oral Soluble Film (ROSF) was administered to 16 subjects in pilot bioavailability 
study (Study 1897) that evaluated the bioavailability of a single dose of ROSF 50mg 
compared to a single dose of Rilutek® 50mg. Sixteen (16) subjects experienced a total of 4 
adverse events over the course of the study, all mild in severity. The most common was 
somnolence, occurring in 2 subjects who received the ROSF and 2 subjects who received the 
Rilutek® 5 mg dose (Table 1). There were no AEs in clinical laboratory tests and there were 
no Serious Adverse Events (SAEs), or deaths. All formulations of the test and reference 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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Page 24 of 55 
 
 
products were well tolerated. Inspections of the oral cavity were conducted before 
application, and after disintegration/dissolution of the ROSF without evidence of local 
irritation or adverse events related to the application.  
 
Table 1: Adverse Event Listings from Pilot Bioavailability Study 1897 with Riluzole 
Oral Soluble Film 
Subj 
No. Period TRT 
Adverse 
Event 
MedDRA 
Onset 
Date 
(MMM-
DD-
YYY) 
Onset 
Time 
(HH:MM) 
Resolu-
tion  
Time 
(HH:MM) 
Time 
from 
Dosing  
(h) 
Dura-
tion  
(h) 
Severity 
Action 
Taken 
Related  
to Study 
Drug 
Preferred 
Term 
System  
Organ 
Classification 
07 
2 
A Sleepiness Somnolence Nervous system 
disorders 
Nov-09-
2015 
09:30 
Nov-09-
2015 
2.28 
1.00 
Mild 
None 
Possible 
05 
3 
C Sleepiness Somnolence Nervous system 
disorders 
Nov-17-
2015 
08:35 
Nov-17-
2015 
1.43 
0.67 
Mild 
None 
Probable 
06 
1 
D 
Nausea 
Nausea 
Gastrointestinal  
disorders 
Nov-02-
2015 
07:15 
Nov-02-
2015 
0.07 
0.25 
Mild 
None 
Probable 
10 
2 
D Sleepiness Somnolence Nervous system 
disorders 
Nov-09-
2015 
10:30 
Nov-09-
2015 
3.18 
0.58 
Mild 
None 
Possible 
TRT = Treatment: A = ROSF 50mg administered without water; B = ROSF 50mg administered with 240 mL of 
water; C = Rilutek® 50mg intact tablet administered with 240 mL of water; D = Rilutek® 50mg crushed 
with 15ml applesauce. 
Source: CSR 1897, Section 16.2.7 
7. 
STUDY OBJECTIVES 
7.1. 
Primary Objectives 
Riluzole is FDA-approved for the treatment of patients with Amyotrophic Lateral Sclerosis 
(ALS). Riluzole extends survival and/or time to tracheostomy. ROSF (MonoSol Rx LLC) is 
a new formulation of riluzole that allows for rapid dissolution and release of active drug in 
the oral cavity. Since circumoral paresthesia and dry mouth have been reported with riluzole 
administered as Rilutek® tablets, the primary objective is to evaluate the effect, if any, of the 
new ROSF formulation on swallowing safety in subjects with ALS.  
STUDY DESIGN 
Approximately 30 subjects with ALS will be enrolled and undergo an instrumental 
evaluation of swallowing safety before and after administration of a single dose of the ROSF 
formulation containing 50mg of riluzole.   


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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8. 
SELECTION AND ENROLLMENT OF SUBJECTS 
8.1. 
Inclusion Criteria and Exclusion Criteria 
8.1.1. 
Inclusion Criteria: 
Subjects meeting all of the following criteria may be included in the study: 
1. Male or female subjects between 18-80 years of age, inclusive 
2. Subjects with a diagnosis of probable or definite ALS in accordance with the 
Revisited El-Escorial Criteria (Cedarbaum, 1999) 
3. Subjects must be currently on an oral diet and able to take foods and liquids by mouth 
equivalent to a score of 3 or above on the Functional Oral Intake Scale (Crary, 2005).  
4. Subjects with no known allergy to barium, riluzole or inactive ingredients* in ROSF 
5. Subjects or subject’s legally authorized representative must be willing and able to 
give informed consent/assent and HIPAA authorization.  
6. Subjects must have the ability to comprehend and be informed of the nature of the 
study, as assessed by the PI or Sub-Investigator. 
7. Subjects prescribed riluzole at or before the dose of study drug. (The study is open to 
subjects currently taking riluzole at screening, subjects who are not currently taking 
riluzole at screening who have taken riluzole in the past, and subjects to be newly 
started on riluzole (given as ROSF in this study.) 
8. Female subjects of childbearing potential must have a negative urine pregnancy test at 
Screening and Visit 1.  Female subjects of childbearing potential (i.e. not surgically 
sterile, not 2 years postmenopausal, or not with a sterile partner) must have a negative 
pregnancy test at screening and Visit 1, agree to abstinence, be practicing double 
barrier contraception or using an FDA approved contraceptive (e.g., licensed 
hormonal or barrier methods) for greater than 2 months prior to screening visit and 
commit to an acceptable form of birth control for the duration of the study and for 30 
days after participation in the study   
9. Availability to volunteer for the entire study duration and willing to adhere to all 
protocol requirements 
 
*See Investigator Brochure 
8.1.2. 
Exclusion Criteria: 
Potential subjects meeting any of the following criteria will be excluded: 
1. Subjects who score 2 or below on the Functional Oral Intake Scale  (Crary, 
2005)    


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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2. Subjects with a prior swallowing study that has shown a PAS of 3 or greater 
3. Subjects with a history of two or more episodes of aspiration pneumonia 
requiring hospitalization 
4. Subjects with a history of clinically significant liver disease, renal disease, or any 
other medical condition judged to be exclusionary by the investigator 
5. Subjects who are unwilling to sign informed consent or subjects who for any 
other reason in the judgment of investigator are unable to complete the study 
6. Female subjects who have a positive urine pregnancy test (βhCG) at screening or 
Visit 1, are trying to become pregnant or are breastfeeding. 
7. Subjects with active cancer within the previous 2 years, except treated basal cell 
carcinoma of the skin 
8. Subjects who have taken any experimental drug within 30 days prior to 
enrollment or within 5 half-lives of the investigational drug –whichever is the 
longer period.  However, subjects who have previously completed other 
MonoSol Rx sponsored ROSF clinical studies within the last 30 days prior to 
enrollment may be eligible for consideration for entry into this study. 
9. Subjects with moderate or severe renal impairment as defined by a calculated 
creatinine clearance of ≤50 mL/minute 
10. Subjects currently taking riluzole with ALT levels greater than 5 times upper 
limit of normal or with evidence of clinical jaundice.  (Riluzole should be 
discontinued in these patients.)  
11. Subjects who will be receiving riluzole for the first time who exhibit baseline 
elevations of several LFTs (especially elevated bilirubin). (These findings at 
baseline should preclude the use of riluzole including ROSF).  
12. Use of potentially hepatotoxic drugs: (e.g., allopurinol, methyldopa, 
sulfasalazine). 
13. Subjects with clinically significant abnormal laboratory values in the judgment 
of the investigator 
14. Use of strong or moderate CYP1A2 inhibitors (e.g., ciprofloxacin, enoxacin, 
fluvoxamine, methoxsalen, mexiletine, thiabendazole, vemurafenib, zileuton) 
and CYP1A2 inducers (e.g. rifampin and barbiturates) in the previous 30 days 
before first drug administration. 
15. Anything else that, in the opinion of the investigator, would place the subject at 
increased risk or preclude the subject’s full compliance with or completion of the 
study 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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16. Employee or immediate relative of an employee of the investigator, MonoSol Rx 
LLC, any of its affiliates or partners, or inVentiv Health. 
8.2. 
Subject Withdrawal  
Inclusion in the study is entirely voluntary and subjects may withdraw at any time for any 
reason. Possible reasons for withdrawal are serious adverse events, adverse events, and 
subject’s choice.  Subjects who elect to withdraw from the study after taking study 
medication but prior to completion of the VFSS 2-PAS will be asked to comply with end of 
study clinical laboratory evaluation(s).  For a complete list of all tests to be performed, see 
Section 10.3.7, Laboratory Evaluations.  Subjects who withdraw due to an adverse event will 
be followed whenever possible until resolution of the adverse event. It may be appropriate 
for the subject to return to the site 2 weeks after the subject is off study to evaluate for 
resolution of any adverse events and to receive further information about options for future 
clinical care.  The Investigator will decide the course of action. 
8.3. 
Study Enrollment Procedures 
The following screen procedures will be conducted on each potential subject: 
• Obtain informed consent as evidenced by subject or subject’s legally authorized 
representative signing an informed consent. Informed consent will be signed prior 
to any study-related procedures and prior to screening per protocol. Informed 
consent will be obtained by the site PI and/or his or her designee.  
• Record medical history 
• Documentation of disease 
• Obtain vital signs (temperature, respiratory rate (RR), heart rate (HR), blood 
pressure (BP), height and weight 
• Collect blood and urine for baseline clinical laboratory evaluation(s) and urine 
pregnancy test (females of childbearing potential only). For a complete list of all 
tests to be performed, see Section 10.3.7, Laboratory Evaluations. 
• Complete physical and neurological examinations 
• ALS Functional Rating Scale-Revised  (ALSFRS-R) 
• Eating Assessment Tool-10 (EAT-10) 
• Functional Oral Intake Scale (FOIS) 
• Collection of pretreatment AEs, if subject receiving riluzole pre study  
• Principal Investigator’s/Sub-Investigator’s review of Inclusion/Exclusion criteria 
and all screening results/data to assess eligibility of each potential subject 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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• Record/Review concomitant medications 
Screening procedures will be completed within 28 days of Visit 1.  
8.3.1. 
Subject Recruitment and Retention 
Participants will be recruited from patients followed in the neuromuscular programs at The 
University of Florida. Potential participants will be contacted by the investigators or their 
staff and invited to participate. These recruitment strategies will include a mechanism by 
which the subjects can provide their contact information.  
8.3.2. 
Screening Logs 
Screening logs to document reasons for ineligibility and reasons for nonparticipation of 
eligible subjects will be maintained to document number of subjects referred, referral source, 
number screened, number failed due to ineligibility or nonparticipation of eligible subjects, 
and reasons for ineligibility or nonparticipation of eligible subjects.  
8.3.3. 
Randomization/Treatment Assignment 
Randomization is not applicable. This is an open label swallowing safety and tolerability 
trial. 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
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9. 
DRUG PRODUCT 
9.1. 
Drug Information 
 
Table 2 Drug Information 
Treatment 
 
Drug Name 
Riluzole 
Strength 
50mg 
Dosage Form 
Oral Soluble Film 
Manufacturer 
MonoSol Rx LLC 
Dose 
1 x 50mg  
9.2. 
Handling of Study Drug, Packaging and Labeling 
The Sponsor will supply a sufficient quantity of the study drug to allow completion of this 
study including some excess for replacement if needed.  The study drug will be sent to the 
Investigator packed in individual unit-dose packages.  Each unit-dose package will be labeled 
in English containing at minimum:  Protocol Number, Drug Name, Strength, Route of 
Administration, and statements “Caution: New Drug – Limited by United States Law to 
Investigational Use Only”, “Keep Out of Reach of Children”, storage conditions and 
batch/lot number. The site pharmacies will keep a log of study drug kits received and 
dispensed identified by subject ID, subject initials, and date dispensed. Study drug will be 
stored at room temperature in a double-locked room or on-site pharmacy as directed by 
institutional SOP. The site pharmacist or coordinator as indicated in the delegation log will 
dispense study drug at the study visit.  This is a single dose study. The dose of study drug 
will not be adjusted.   
In accordance with local regulatory requirements, the investigator, designated site staff, or 
head of the medical institution (where applicable) must document the quantity of 
investigational product administered to study subjects, the quantity received, and the quantity 
destroyed upon completion of the study. The investigator is responsible for ensuring product 
accountability records are maintained throughout the course of the study. The inventory 
record will include details of MonoSol Rx study drug received and dispensed to subjects, 
batch, and ID numbers will be maintained by the Investigator.  
At the completion of the study, all unused study drug, including any excess, will be retained 
by the Investigator until the authorization to return or destroy is received from the Sponsor. 
An accounting must be made of any drug deliberately or accidentally destroyed.  


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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9.3. 
Concomitant Interventions 
All concomitant medications received by a subject during participation in the study will be 
recorded on the appropriate source documents.  
9.3.1. 
Required Concomitant Medications/Interventions 
No concomitant medications or interventions are required per protocol. 
The study is open to subjects currently taking riluzole at screening, subjects who are not 
currently taking riluzole at screening who have taken riluzole in the past, and subjects to be 
newly started on riluzole (given as ROSF at the start of this study.)  
9.3.2. 
Prohibited Medications/Interventions 
Concomitant medications and interventions will be reviewed at screening and Visit 1. The 
investigator may choose to exclude a subject from participation if a concomitant medication 
or intervention is judged likely to interfere with the study objectives or to affect the subject’s 
safety. 
The following drugs are known to interact with riluzole (Rilutek® tablets US Package Insert; 
revision 04/2016) and should not be administered with ROSF: 
• Agents that may increase riluzole blood concentration; Strong or moderate CYP1A2 
inhibitors (e.g., ciprofloxacin, enoxacin, fluvoxamine, methoxsalen, mexiletine, 
thiabendazole, vemurafenib, zileuton). 
• Agents that may decrease riluzole plasma concentrations: CYP1A2 inducers (e.g. 
rifampin and barbiturates) 
• Potentially hepatotoxic drugs: (e.g., allopurinol, methyldopa, sulfasalazine) 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
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10. 
STUDY PROCEDURES 
10.1. 
Schedule of Activities 
The schedule of study activities is presented in Table 3. 
Table 3 Schedule of Activities 
Evaluation  
Screening 
Visit 1 
Written Informed Consent  
X 
 
Inclusion/Exclusion Review 
X 
Xa 
Documentation of Disease 
X 
 
Record/Review Concomitant Medications 
X 
Xa 
Medical History/ Demographics 
X 
 
Height and Weight 
X 
 
Vital Signs – HR, BP, RR  
 
Xb 
Vital Signs – HR, BP, RR and temperature 
X 
Xa 
Comprehensive Physical Exam 
X 
 
Brief Physical Exam 
 
Xb 
Neurological Examination 
X 
 
Brief Neurological Exam 
 
Xb 
Eating Assessment Tool-10 (EAT-10) 
X 
Xa 
Functional Oral Intake Scale (FOIS) 
X 
Xa 
ALS Functional Rating Scale - Revised (ALSFRS-R) 
X 
Xa 
Oral Examination  
X 
Xc 
VFSS 1 - Penetration-Aspiration Scale (pre-dose) 
 
X 
VFSS 2 - Penetration-Aspiration Scale (post-dose) 
 
X 
Clinical laboratory evaluation(s)hematology, chemistry, 
urinalysis)d 
X 
Xb 
Urine Pregnancy Test (females of childbearing potential) 
X 
Xa 
Adverse Event 
X 
Xc 
Dispense Study Drug (one dose)  
 
X 
aBefore VFSS 1 procedure 
bAfter VFSS 2 procedure 
cBoth – before VFSS 1 procedure and after VFSS 2 procedure 
dSee Section10.3.7 Laboratory Evaluations 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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10.2. 
Timing of Study Activities 
No study procedures will be performed prior to the signing of the Informed Consent Form 
(ICF). All subjects will sign an ICF prior to undergoing any study tests or procedures. 
Visit 1 should occur within 28 days of the Screening Visit.   
Inclusion in the study is entirely voluntary and subjects may withdraw at any time for any 
reason. Possible reason for withdrawal could include serious adverse events, adverse events, 
and subject’s choice.  Subjects who elect to discontinue medication will be asked to comply 
with end of study clinical laboratory evaluation(s) and urine pregnancy test (females of 
childbearing potential).  For a complete list of all clinical laboratory evaluation(s) to be 
performed, see Section 10.3.7, Laboratory Evaluations. Subjects who withdraw due to an 
adverse event will be followed whenever possible until resolution of the adverse event. It 
may be appropriate for the subject to return to the site 2 weeks after the subject is off study to 
evaluate for resolution of any adverse events and to receive further information about options 
for future clinical care.  The Investigator will decide the course of action. 
10.2.1. 
Screening procedures 
At the screening visit, potential subjects will be informed about study procedures and will 
then sign an informed consent form.  Inclusion/exclusion criteria will be reviewed and a 
medical history and full physical examination completed. Vital signs, weight, height and 
concomitant medications will be recorded. Clinical laboratory tests will be performed 
including complete blood count (CBC) with differential, electrolytes, BUN, creatinine, ALT, 
AST, total bilirubin, albumin, and a pregnancy test for women of childbearing potential.  
The following procedures will be performed during the screening visit: 
• Informed consent 
• Inclusion/exclusion assessment 
• Documentation of Disease 
• Medical history 
• Record concomitant medications 
• Clinical laboratory evaluation(s)see Section 10.3.7 Laboratory Evaluations 
• Urine pregnancy test (females of childbearing potential) 
• Height and weight 
• Vital signs (including temperature) 
• Comprehensive physical and neurological examinations including oral 
examination 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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• ALS Functional Rating Scale-Revised (ALSFRS-R) 
• Eating Assessment Tool-10 (EAT-10) 
• Functional Oral Intake Scale (FOIS) 
• Adverse event review, if subject is currently on riluzole  
All inclusion and exclusion criteria and clinical laboratory tests will be reviewed by the 
investigator prior to scheduling the baseline visit (; Schedule of Activities; Visit 1).  A log 
will be kept at the site to record all subjects screened for entry into the study. This 
information will also be captured electronically in the electronic data capture system (EDC). 
Demographic characteristics of all subjects who are screened will be recorded whether or not 
they qualify for entry into the study. The reason for non-qualification will be recorded for all 
subjects who are not eligible. The reason for nonparticipation will also be recorded for 
subjects who are eligible but choose not to participate in the trial. If a subject fails screening 
for the study, the subject can be re-screened if the investigator determines it is appropriate to 
do so. At any time during the study, repeat laboratory tests may be obtained if the 
investigator or central laboratory believes that a laboratory test result is in error. Additional 
laboratory tests may also be obtained at any time during the study, at the discretion of the 
investigator. 
10.2.2. 
On-Study/On-Intervention Evaluations/Procedures 
10.2.2.1. Baseline (Day 0,Visit 1):  
The baseline visit (Day 0, Visit 1) will include a single dose of study drug. It will be 
scheduled within 28 days after the screening visit. At this visit, inclusion/exclusion criteria 
and concomitant medications will be reviewed. Vital signs, brief physical and neurologic 
examination, as well as study questionnaires and testing will be performed as noted in Table-
3; Schedule of Activities. 
The following documentation and procedures will be performed at Day 0 (Visit 1): 
• Adverse event review (before VFSS 1 procedure and after VFSS2 procedure) 
• Inclusion/exclusion assessment (before VFSS 1 procedure) 
• Concomitant medications (before VFSS 1 procedure) 
• Urine pregnancy test for females of childbearing potential (before VFSS 1 procedure) 
• Vital signs  HR, BP, RR and temperature (before VFSS 1 procedure) 
• Vital Signs HR, BP, RR (after VFSS 2 procedure) 
• Oral Exam (before VFSS 1 procedure and after VFSS 2 procedure) 
• Videofluoroscopy Swallow Study 1 (VFSS 1; pre dose procedure) 
• Administer study drug (one dose)  
• Videofluoroscopy Swallow Study 2 (VFSS 2; post dose procedure) 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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• Brief physical exam (after VFSS 2 procedure) 
• Brief neurologic exam (after VFSS 2 procedure) 
• Clinical laboratory evaluation(s) see Section 10.3.7 Laboratory Evaluations (after 
VFSS 2 procedure) 
Videofluoroscopy Swallow Study (VFSS 1-PAS) 
Subjects will undergo a standardized videofluoroscopic swallowing study (VFSS) for direct 
visualization of the swallowing process and any episodes of penetration or aspiration. The 
VFSS represents the gold standard swallowing exam to directly visualize swallowing and 
specifically aspiration during swallowing. After consent has been verified and screens 
completed, the patient will be seated and will complete a standardized bolus protocol that 
includes 12 bolus trial presentations in the following order: 
1. 5ml thin liquid barium 
2. 5ml thin liquid barium 
3. 5ml thin liquid barium 
4. Regular sip of thin liquid taken from a cup containing 60cc of thin liquid. 
5. Consecutive cup sips of remaining thin liquid barium 
6. Tablespoon of thin honey consistency barium 
7. Tablespoon of thin honey consistency barium 
8. Tablespoon of thin honey consistency barium 
9. Tablespoon of pudding consistency barium. 
10. Tablespoon of pudding consistency barium. 
11. Graham cracker with pudding-thick barium. 
12. 13 mm barium tablet (EZ-Disk) with water.  
A standard ‘bail out’ criteria used on all VFSS protocols in the Swallowing Systems Core 
laboratory will be utilized in this study. This represents a standard provision to avoid 
unnecessary risk to research subjects during VFSS exams and will include cessation of bolus 
presentations during a specific VFSS test (i.e. either VFSS 1 or VFSS 2) on the third episode 
of frank aspiration (material entering the airway below the level of the true vocal folds) or 
residue greater than 75% of either vallecular or pyriform housing that is unable to be cleared 
by the patient with prompting and strategies. The potential for this to occur is factored into 
the targeted enrollment of approximately 30 subjects in an effort to complete 25 subjects for 
the swallowing evaluation consistent with the sample size estimation (Section 13.5.3; 
Power).  
The start time and finish time for the standardized bolus protocol will be recorded for both 
VFSS 1 and VFSS 2. 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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Immediately following VFSS 1-PAS, the patient will then be administered ROSF on the 
dorsum of tongue along the median lingual sulcus, and the time of administration will be 
recorded (Appendix B). Following a three-minute time interval the investigator will confirm 
that the ROSF has dissolved and VFSS 2-PAS will be performed. If ROSF is not fully 
dissolved at 3 minutes, start of the second VFSS 2-PAS bolus protocol will be delayed until 
investigator confirms that ROSF is fully dissolved. The investigator should record whether or 
not ROSF is fully dissolved at 3 minutes after dosing. In the event that ROSF is not fully 
dissolved at 3 minutes, the investigator will record the time that it is confirmed that ROSF is 
fully dissolved. 
Videofluoroscopy Swallow Study Test 2-PAS (VFSS 2-PAS) 
The identical VFSS standardized bolus protocol exam will be performed provided that the 
subject did not demonstrate frank, gross and observable silent aspiration during VFSS 1-PAS 
and provided that the subject’s PAS score in baseline test is 7 or below. VFSS will be 
performed using a Phillips BV Endura fluoroscopic C-arm unit (GE OEC 8800 Digital 
Mobile C-Arm system type 718074) that is housed within the PI’s laboratory and used 
exclusively for research purposes. Fluoroscopic data will be captured in high resolution at 30 
frames per second and in the lateral field of view using a TIMS Dicom (Version 3.2, TIMS 
Medical, TM, Chelmsford, MA). 
The identical standard patient safety bail out criterion will be enforced in VFSS 2. This 
includes cessation of the specific testing phase on the third episode of frank aspiration or 
residue greater than 75% of either vallecular or pyriform housing that is unable to be cleared 
by the patient with prompting and strategies. Once the study is completed, recordings will be 
saved and digitally backed up for subsequent analyses of the PAS. Although this study is 
specifically investigating swallowing safety, this bailout criterion will still allow the study of 
up to three potential episodes of aspiration so that assessing impact on swallowing safety is 
still feasible while maintaining patient safety.   
Missed Visit 1: When a subject fails to appear for scheduled Visit 1, the site will contact the 
subject. The site will stress the importance of the evaluation and reschedule within the 28-
day window if possible. 
10.2.3. 
Study Medication/Intervention Discontinuation Evaluations/Procedures 
Inclusion in the study is entirely voluntary and subjects may withdraw at any time for any 
reason. Possible reason for withdrawal could include serious adverse events, adverse events, 
and subject’s choice.  Subjects who decide to discontinue the study either after receiving the 
VFSS 1-PAS procedure but before receiving study medication or after receiving study drug 
and before VFSS 2-PAS procedure will be asked to comply with end of study clinical 
laboratory evaluation(s) see Section 10.3.7 Laboratory Evaluations. Subjects who withdraw 
due to an adverse event will be followed, whenever possible, until resolution of the adverse 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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Riluzole Oral Soluble Film 
 
 
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Page 36 of 55 
 
 
event. It may be appropriate for the subject to return to the site 2 weeks after the subject is off 
study to evaluate for resolution of any adverse events and to receive further information 
about options for future clinical care.  The Investigator will decide the course of action. 
All serious adverse events (SAEs), whether or not the event is deemed drug-related, will be 
reported on the SAE Report Form by email or fax to the designated Clinical Research 
Organization, inVentiv Health, within twenty-four hours (24) of the Investigator being aware 
of SAE (Section 12.3; Procedures for Reporting Adverse Events) and inVentiv will report to 
the Sponsor. 
10.2.4. 
On Study/Off-Intervention Evaluations 
Subjects who discontinue the study for any reason either after receiving the VFSS 1-PAS 
procedure but before receiving study medication or after receiving study drug and before the 
VFSS 2-PAS procedure will be asked to comply with end of study clinical laboratory 
evaluation(s); see Section 10.3.7 Laboratory Evaluations.  Subjects who withdraw due to an 
adverse event will be followed whenever possible until resolution of the adverse event. It 
may be appropriate for the subject to return to the site 2 weeks after the subject is off study to 
evaluate for resolution of any adverse events and to receive further information about options 
for future clinical care.  The Investigator will decide the course of action. 
10.2.5. 
Final On-Study Evaluations 
The subject will be followed after Visit #1 for resolution of adverse events. If the subject 
decided to discontinue the study either after receiving the VFSS 1-PAS procedure but before 
receiving study medication or after receiving study drug and before VFSS 2- PAS procedure, 
the subject will be asked to comply with end of study clinical laboratory evaluation(s); see 
Section 10.3.7 Laboratory Evaluations. 
10.2.6. 
Off-Study Requirements 
Subjects who withdraw due to an adverse event will be followed whenever possible until 
resolution of the adverse event. It may be appropriate for the subject to return to the site 2 
weeks after the subject is off study to evaluate for resolution of any adverse events and to 
receive further information about options for future clinical care.  The Investigator will 
decide the course of action. 
10.2.7. 
Pregnancy 
Women who are pregnant will not be enrolled in the study.  Riluzole has not been studied in 
pregnancy and the Rilutek® US Package Insert notes that based on animal studies riluzole 
may cause fetal harm.  Following administration of study drug, any known cases of 
pregnancy in female subjects or female partners of male subjects, will be reported until 30 
days after the subject completes or withdraws from the study.  The pregnancy will be 
reported immediately by phone and by faxing/emailing a completed Pregnancy Report to the 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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Page 37 of 55 
 
 
Sponsor (or designee) within 24 hours of knowledge of the event.  (Section 12.3; Procedures 
for Reporting Adverse Events) 
10.3. 
SPECIAL INSTRUCTIONS AND DEFINITIONS OF 
EVALUATIONS 
10.3.1. 
Protocol Deviations  
Missed visits and any procedures not performed (not attempted) for any reason will be 
reported as protocol deviations. Details regarding any deviations will be documented. 
10.3.2. 
Documentation of Amyotrophic Lateral Sclerosis 
To be eligible for participation in this trial, participants must have ALS defined as probable 
or definite ALS in accordance with the Revisited El-Escorial Criteria (Cedarbaum, 1999). 
These criteria will be clearly designated on source documentation and in the electronic case 
report forms (eCRFs). 
10.3.3. 
Medical History 
A comprehensive medical history will be obtained at the screening visit and reviewed for any 
exclusionary criteria. 
10.3.4. 
Treatment History 
Medications will be reviewed for concomitant therapies that would be exclusionary. 
10.3.5. 
Concomitant Medications/Treatments 
Current medications will be reviewed for contraindicated therapies.   
10.3.6. 
Clinical Assessments 
10.3.6.1. Physical and Neurological Examination 
 
Subjects will undergo a comprehensive physical and neurological examination at screening, 
and a brief physical and neurological examination at Visit 1 following the second VFSS.   
The comprehensive physical examination will include complete vital signs, weight, height, 
general appearance, and evaluation of systems: head, ears, eyes, nose, and throat; respiratory; 
abdomen; lymph nodes; spine; skin; cardiovascular; and extremities.  The brief general 
physical examination will include abbreviated vital signs (blood pressure, heart rate, 
respiratory rate), and examination of the cardiovascular and respiratory systems and 
abdomen. Other elements may be included depending on symptoms or physical findings. 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
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The comprehensive neurological examination will include (as permitted by the patient’s 
capabilities) cranial nerves 2-12, muscle tone and strength, tendon reflexes and plantar 
response, sensory function (pain, light touch, position, vibration), coordination (finger-nose), 
and gait.  The brief neurological examination will include cranial nerves 2-12, muscle 
strength, tendon reflexes, plantar response, and sensory function (pain, light touch, position, 
vibration).  Other elements may be included depending on symptoms or physical findings 
10.3.6.2. Primary Outcome Variable: Videofluoroscopy Swallow Study – Penetration 
Aspiration Scale (VFSS - (PAS)). 
The primary objective is to evaluate the effect, if any, of the new ROSF formulation on 
swallowing safety in subjects with ALS. The primary outcome is the difference in PAS 
Scores obtained before and after ROSF administration.  
The validated penetration aspiration scale (PAS) is a direct measure of swallowing safety. 
The PAS is an 8-point validated scale of swallow safety that takes into account both 
degree/level of airway invasion during swallowing and the patient’s response to the 
penetration or aspiration episode. The PAS scale is provided in Table 4 (Rosenbek, 1996) 
with VFSS lateral image examples recorded and analyzed from our laboratory to provide 
examples of each type of swallow on the right-hand panel. 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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Table 4 Penetration Aspiration Scale (PAS) 
 
The inclusion criteria are developed to focus the study on a cross section of ALS subjects. 
Exclusion criteria exclude subjects with certain medical conditions, with allergies to barium 
or study drug, and females who are pregnant or breastfeeding.  
The primary aim of this study is to assess swallowing safety with the new ROSF formulation. 
10.3.7. 
Laboratory Evaluations 
Blood and urine specimens will be collected by qualified study center personnel at screening 
and visit 1 as described under Section 10.0 Study Procedures and sent to the lab for analysis.  
Clinical laboratory evaluation(s) are conducted at the screening visit and Visit 1(after VFSS 
2 procedure).   A urine pregnancy test (females of child bearing potential only) will be 
conducted at the screening visit and at Visit 1 (before VFSS 1 procedure).  The clinical 
laboratory evaluation(s) are presented in Table 5. 
If the subject decided to discontinue the study either after receiving the VFSS 1-PAS 
procedure but before receiving study medication or after receiving study drug and before the 
VFSS 2- PAS procedure, the subject will be asked to comply with end of study clinical 
laboratory evaluation(s) presented in Table 5. 
 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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Table 5 Clinical Laboratory Evaluation(s) 
Hematology 
Serum Chemistry Urine 
Complete Blood Count 
with Differential 
Electrolytes 
Urinalysis 
BUN 
Pregnancy Test (females of 
childbearing potential) 
Creatinine 
ALT 
AST 
Total Bilirubin 
Albumin 
 
Abnormal laboratory test results or a positive urine pregnancy test will be flagged by the 
laboratory.  All clinically important abnormal laboratory tests occurring during the study will 
be repeated if appropriate and followed until resolution (return to normal or baseline values) 
or stabilize, or until they are considered by the Investigator to be no longer clinically 
significant. 
10.3.8. 
ALS Functional Rating Scale – Revised (ALSFRS-R) Questionnaire  
The ALSFRS-R is a quickly administered (5 minute) ordinal rating scale (ratings 0-4) used to 
determine subjects’ assessment of their capability and independence in 12 functional 
activities/questions (Cedarbaum, 1999). All 12 activities are relevant in ALS. Initial validity 
was established by documenting that in subjects with ALS, change in ALSFRS-R scores 
correlated with change in strength over time, was closely associated with quality of life 
measures, and predicted survival (Appendix A). The test-retest reliability is greater than 0.88 
for all test items. The advantages of the ALSFRS-R are that the categories are relevant to 
ALS; it is a sensitive and reliable tool for assessing activities of daily living function in 
subjects with ALS; and it is quickly administered. In a recent trial employing the ALSFRS as 
a secondary outcome measure, placebo-treated patients showed a decline of 0.92 units per 
month, with a standard error of 0.08. With appropriate training the ALSFRS-R can be 
administered with high inter-rater reliability and test retest reliability. 
10.3.9. 
 Eating Assessment Tool -10  (EAT-10) 
EAT-10: The Eating Assessment Tool-10, is a validated 10-item patient report scale of 
perceived swallowing impairment (Belafsky et al. 2008).  The EAT-10 uses a 5-point ordinal 
rating scale where a patient rates their perceived degree of impairment for each item from 0 
(no impairment) to 4 (severe impairment) for a total range of scores between 0 (no perceived 
swallowing impairment) to 40 (severe impairment) (Appendix C).  The P.I of this study 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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recently determined that the EAT-10 was sensitive to identify ALS patients with severe 
dysphagia including aspiration. A Receiver Operating Curve analysis revealed that a cut 
point of 8 on the EAT-10 yielded a sensitivity of 86%, specificity of 72%, likelihood ratio of 
3.1, and negative predictive value of 95.5% for detecting aspiration in ALS (Plowman et al., 
2016). 
10.3.10. 
Functional Oral Intake Scale (FOIS) 
The FOIS is a simple 7 point scale that describes the subject’s functional status with respect 
to oral intake, ranging from 1 (No oral intake) to 7 (Total oral intake with no restrictions) 
(Appendix D) (Crary, 2005). 
10.3.11. 
Subject Adherence Assessments 
Adherence to study requirements and compliance with concomitant medication restrictions 
will be assessed Visit 1 through direct questioning by study personnel.  
10.3.12. 
Physical and Neurological Examination 
Subjects will undergo a comprehensive physical and neurological examination at screening, 
and a brief physical and neurological examination at Visit 1 following the second VFSS.   
The comprehensive physical examination will include complete vital signs, weight, height, 
general appearance, and evaluation of systems: head, ears, eyes, nose, and throat; respiratory; 
abdomen; lymph nodes; spine; skin; cardiovascular; and extremities.  The brief general 
physical examination will include abbreviated vital signs (blood pressure, heart rate, 
respiratory rate), and examination of the cardiovascular and respiratory systems and 
abdomen. Other elements may be included depending on symptoms or physical findings. 
The comprehensive neurological examination will include (as permitted by the patient’s 
capabilities) cranial nerves 2-12, muscle tone and strength, tendon reflexes and plantar 
response, sensory function (pain, light touch, position, vibration), coordination (finger-nose), 
and gait.  The brief neurological examination will include cranial nerves 2-12, muscle 
strength, tendon reflexes, plantar response, and sensory function (pain, light touch, position, 
vibration).  Other elements may be included depending on symptoms or physical findings. 
11. 
SAFETY AND ADVERSE EVENTS 
The PI will carefully monitor each subject throughout the study for possible AEs. All AEs 
will be documented on CRFs designed specifically for this purpose. All AEs will be reported 
whether serious or non-serious.   


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
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11.1. 
Adverse Experience Reporting and Follow Up 
Subjects will be instructed to inform clinic personnel of any untoward medical symptoms 
and/or events that may arise during the course of the study.  If an adverse event is 
experienced by a subject, then the subject will be questioned concerning symptoms that may 
have occurred after the administration of the study drug.  The incidence, severity and 
duration of all AEs will be recorded according to the following scale: 
Mild 
Adverse event resulting in discomfort, but not sufficient to cause 
interference in normal daily activities 
Moderate 
Adverse event resulting in discomfort that is sufficient to cause 
interference in daily activities. 
Severe 
Adverse event resulting in discomfort causing an inability to carry out 
normal daily activities 
 
Subjects who withdraw due to an adverse event will be followed whenever possible until 
resolution of the adverse event. It may be appropriate for the subject to return to the site 2 
weeks after the subject is off study to evaluate for resolution of any adverse events and to 
receive further information about options for future clinical care.  The Investigator will 
decide the course of action. 
 
11.2. 
Assessing Relationship to Study Drug 
The Principal Investigator/Sub Investigator will assess the relationship of all adverse 
reactions to the drug, using the following scale: 
 
Probable 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to drug administration, unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and which 
follows a clinically reasonable response on withdrawal. 
Possible 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to drug administration, but which could also 
be explained by concurrent disease or other drugs or chemicals.  
Information on drug withdrawal may be lacking or unclear. 
Unlikely 
A clinical event, including laboratory test abnormality, with a 
temporal relationship to drug administration which makes a causal 
relationship improbable, and which other drugs, chemicals or 
underlying disease provide plausible explanation. 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
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Unrelated 
This category is applicable to AEs which are judged to be clearly and 
incontrovertibly due to extraneous causes (diseases, environment, etc.) 
and do not meet the criteria for drug relationship listed for the above 
mentioned conditions. 
 
Any AEs, whether serious or non-serious, will be monitored throughout the study and 
followed to resolution, when possible, regardless of whether the subject is still participating 
in the study. Subjects who withdraw due to an adverse event will be followed whenever 
possible until resolution of the adverse event. It may be appropriate for the subject to return 
to the site 2 weeks after the subject is off study to evaluate for resolution of any adverse 
events and to receive further information about options for future clinical care.  The 
Investigator will decide the course of action. 
11.3. 
Procedures for Reporting Adverse Events 
Subjects will be instructed to inform clinic personnel of the AEs that may arise during the 
course of the study.  Treatment of any AEs will be administered under the direction of the 
Investigator. 
All symptoms will be recorded by clinic staff and will be reviewed by the Investigator or 
Sub-Investigator prior to any subsequent dosing. 
When appropriate, medical tests and examinations will be performed to document resolution 
of the event(s). 
Adverse events will be coded into the Preferred Term (PT), classified according to the 
current version of Medical Dictionary for Regulatory Activities (MedDRA) with System 
Organ Classification (SOC) and reported with severity, duration, onset time and relationship 
to study drug and action taken. 
Female subjects of child-bearing potential must have a negative pregnancy test at all visits.  
Following administration of study drug, any known cases of pregnancy in female subjects or 
female partners of male subjects, will be reported until 30 days after the subject completes or 
withdraws from the study.    The pregnancy will be reported immediately by phone and by 
faxing/emailing a completed Pregnancy Report to the Sponsor (or designee) within 24 hours 
of knowledge of the event.  The pregnancy will not be processed as a serious adverse event 
(SAE); however the Investigator will follow the subject until completion of the pregnancy 
and must assess the outcome in the shortest possible time but not more than 30 days after 
completion of pregnancy.  The Investigator should notify the Sponsor (or designee) of the 
pregnancy outcome by submitting a follow-up Pregnancy Report.  If the outcome of the 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or 
therapeutic abortion [any congenital anomaly detected in an aborted fetus is to be 
documented] stillbirth, neonatal death, or congenital anomaly), the Investigator will report 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
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Page 44 of 55 
 
 
the event by phone and by faxing a completed SAE form to the Sponsor (or designee) within 
24 hours of knowledge of the event. 
All serious adverse events (SAEs), whether or not the event is deemed drug-related, will be 
reported on the SAE Report Form by email or fax to the designated Clinical Research 
Organization, inVentiv Health within twenty-four hours of the Investigator being aware of 
SAE and inVentiv will report to the sponsor. 
The safety address where SAE report forms and other SAE related documents should be sent 
is: 
Fax No. +1 866 856 1649 
Email: In case of emergency or fax failure the report can also be submitted by email to 
saereceipt.international @inventivhealth.com 
If notification cannot be made via these means due to technical delivery problems, initial 
notification may be made by phone, using the inVentiv Health GSPV “SAE Hotline” 
number.  A telephone call to the SAE hotline does not substitute for the site’s responsibility 
to submit a written SAE Report Form to inVentiv Health SAEs reported via the Hotline 
number must be followed with the SAE report the same day.  
Hotline No.: 888-750-8020 
In the event of any fatal or life-threatening SAE, the investigator must also inform a Medical 
Monitor at inVentiv Health by telephone or email: 
Jane Williams, MD MPH 
Medical Director, Neuroscience 
Medical and Scientific Affairs 
Tel: +1 978 501-0714 
Email: jane.williams@inventivhealth.com 
Dr. Marcel Reichert 
Medical Director 
Tel: 650-554-1706 
Cellular: 650-550-1706 
Email: marcel.reichert@inventivhealth.com 
 
The Investigator will be responsible for notifying the IRB.  The Sponsor will be responsible 
for notifying the regulatory agencies, as appropriate. 
If a subject experiences a non-serious Adverse Event: 
• All clinical adverse events are recorded in the CRFs designed specifically for this 
purpose. It is important to report all AEs, especially those that result in permanent 
discontinuation of the investigational product being studied, whether serious or non-
serious. 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
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Page 45 of 55 
 
 
• The site should fill out the CRF and enter the non-serious AE information into the 
online Adverse Event Reporting System within 5 working days/7 calendar days of the 
site learning of a new AE or receiving an update on an existing AE.  
Expected adverse events for riluzole are provided in Section 6.4; Safety.   
12. 
CRITERIA FOR INTERVENTION DISCONTINUATION 
A subject will be discontinued from the study under the following circumstances: 
• If the subject is hemodynamically unstable 
• If discontinuation is recommended by treating physician 
• At the subject’s request  
13. 
STATISTICAL CONSIDERATIONS 
13.1. 
General Design Issues 
This open label, single center, single dose study has been designed to evaluate the effect, if 
any, of ROSF, a new formulation riluzole, on swallowing safety in ALS. The study will be 
performed at single center in Gainesville at the University of Florida.  The anticipated time 
from study enrollment until completion of data analyses is approximately 9 months.  The site 
is anticipated to enroll approximately 3-4 ALS subjects per month for a total of 8 months and 
data analysis of raw PAS scoring is anticipated to be conducted over one month.  The 
inclusion criteria are intended to provide a representative cohort of subjects with ALS who 
are currently on an oral diet and able to take foods and liquids by mouth, equivalent to a 
score of 3 or above on the Functional Oral Intake Scale (Crary, 2005).  Eligibility criteria 
exclude subjects with certain medical conditions, allergies to study drug or females that are 
pregnant or breastfeeding.  
The primary aim of this study is to assess swallowing safety with the new ROSF formulation. 
13.2. 
Outcomes 
13.2.1. 
Primary Outcome:  
The primary objective is to evaluate the effect, if any, of the new ROSF formulation on 
swallowing safety in subjects with ALS. The primary outcome is the within subject 
difference in PAS Scores obtained before and after ROSF administration.  
13.3. 
Sample Size and Accrual 
The estimated sample size for this study is 25 completed subjects. Approximately 30 subjects 
will be enrolled. Participants will be recruited from patients followed in the neuromuscular 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
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prohibited without written consent from MonoSol Rx LLC. 
Page 46 of 55 
 
 
program at the University of Florida. Interested participants will be contacted by the 
investigators or their staff and invited to participate. These recruitment strategies will include 
a mechanism by which the subjects can provide their contact information. 
13.4. 
Data Monitoring 
Data Monitoring will be conducted according to Good Clinical Practice and applicable 
government regulations. The investigator agrees to allow monitors access to the clinical 
supplies, dispensing and storage areas, and the clinical files of the study subjects and, if 
requested, agrees to assist the monitors. 
Safety monitoring will include careful assessment and appropriate reporting of adverse 
events. Medical monitoring will include contemporaneous assessment of serious adverse 
events. 
13.5. 
Data Analyses 
13.5.1. 
Penetration Aspiration Scale (PAS) 
Following the examination, each recorded swallow trial will be spliced by bolus trial and 
further by individual swallow and coded for subsequent evaluation. This will include splicing 
and coding of each bolus trial per patient (n=12 per VFSS test). Further, each individual 
swallow within a bolus trial will be analyzed (this can range between 1 to 7 swallows per 
bolus trial). Frame-by-frame analysis at 30 frames per seconds will be utilized. Two 
independent, blinded, and experienced raters from the PI’s laboratory will perform analyses. 
Discrepancies between raters will be flagged and resolved at a consensus meeting and three 
swallows from each evaluation will be repeat rated at random for evaluation of intra-rater 
reliability. 
13.5.2. 
Statistical Analysis 
The within subject difference in PAS scores (before and after ROSF) is the primary outcome 
to assess swallowing safety of ROSF in subjects with amyotrophic lateral sclerosis. Data will 
be analyzed using the non-parametric Wilcoxon Signed-Rank Test. Alpha will be set at 0.05. 
Analysis across each swallowing trial will be performed, providing 12 bolus stimuli trials and 
approximately 35 swallows and PAS scores for each swallow within each participant (across 
various textures and swallowing complexities) to ensure a comprehensive exam across a 
variety of liquid volumes, textures and consistencies).  A sample size of 25 subjects is 
estimated to provide 80% power to detect an intra-subject difference of one point on the PAS 
at the 0.05 level (two-tailed).  Additional details will be provided in the statistical analysis 
plan. 
Depending on the study enrollment rate, the Sponsor may elect to perform an interim 
analysis using available data from the subset of subjects who have completed the study at 
that time.  The results of this interim analysis will be used only for internal planning and 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
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prohibited without written consent from MonoSol Rx LLC. 
Page 47 of 55 
 
 
possibly for sharing with regulatory authorities. The results of the interim analysis will have 
absolutely no influence on the subsequent conduct of the study. 
 
Summary Statistics will be provided for the following: 
• Demographic information 
• Type, incidence, and severity of adverse events 
• Physical and neurological examinations including oral examination 
• Vital signs (heart rate, blood pressure, respiration rate, temperature),  
• Clinical laboratory evaluation(s) and urine pregnancy test (females of childbearing 
potential) 
• ALS Functional Rating Scale – Revised (ALSFRS-R) 
• Eating Assessment Tool -10 (EAT-10) 
• Functional Oral Intake Scale (FOIS) 
13.5.3. 
Power  
Sample size for the present study was determined for a within-subject design (repeated 
measures, same subjects in VFSS 1-PAS and VFSS 2-PAS) at power = 80% and alpha = 0.05 
(G*Power Version 3.1.9.2), assuming a correlation = 0.6 across the two measurements. A 
sample size of n=25 would be able to detect at least 1.0 point difference, effect size 0.6, in 
PAS scores between VFSS 1-PAS and VFSS 2-PAS  (before and after ROSF). It is 
anticipated that approximately 20% of recruited ALS subjects will grossly aspirate during 
VFSS 1-PAS and therefore not have a VFSS 2-PAS performed (for both safety reasons and 
also because VFSS 2-PAS would not yield any useful data due to a ceiling effect).  Therefore 
a total of 30 individuals with ALS will be recruited and enrolled to account for this potential.  
The null hypothesis is no difference in the PAS scores before and after administration of the 
study medication (i.e. PAS scores for VFSS 1-PAS and VFSS 2-PAS). 
14. 
PROTOCOL AMENDMENTS AND STUDY TERMINATION 
All revisions and/or amendments to this protocol must be documented and approved in 
writing by the Investigator and Sponsor. If the revision/amendment will affect subject safety 
and/or study design, then the amendment will be re-submitted to the IRB Authorities for 
approval.  Administrative changes (i.e., typographical errors, discrepancies, clarifications) 
will also be submitted to the IRB, but may not require approval.  A copy of the IRB’s 
approval documents will be included in the final report.   


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
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prohibited without written consent from MonoSol Rx LLC. 
Page 48 of 55 
 
 
It is the Sponsor’s responsibility to submit, or to assign responsibility to submit, all revisions 
and amendments to the appropriate regulatory authorities, when necessary. 
For revisions or amendments to the protocol that substantially alter the study design after 
initiation of the study, the Investigator and Sponsor will decide whether a revised ICF will be 
needed for continued participation. 
The Sponsor and Principle Investigators reserve the right to discontinue the study at the 
clinical study site for safety or administrative reasons at any time. Should the study be 
terminated and/or the clinical study site closed for any reason, all documentation and study 
medication pertaining to the study must be returned to the Sponsor or its representative 
15. 
ETHICAL CONSIDERATIONS  
15.1. 
Basic Principles 
This research will be carried out in accordance with Good Clinical Practice (GCP) as set out 
by the International Council for Harmonization (ICH), the basic principles defined in the 
U.S. Code of Federal Regulations (21 CFR Part 312), the Belmont Report, Directive 
2001/20/EC (Europe), The Tri-Council Policy Statement and the principles enunciated in the 
most recent version of the World Medical Association Declaration of Helsinki. 
15.2. 
 Institutional Review Board Review and Informed Consent 
This protocol and the informed consent document and any subsequent modifications will be 
reviewed and approved by the IRB responsible for oversight of the study. A signed consent 
form, approved by the IRB, will be obtained from the subject by the site PI and/or their IRB-
approved designee.  
For subjects who cannot provide consent for themselves, such as those below the legal age, a 
parent, legal guardian, or person with power of attorney, must sign the consent form; 
additionally, the subject's assent must also be obtained if he or she is able to understand the 
nature, significance, and risks associated with the study.  
Written informed consent will be obtained from each participant before any study-specific 
procedures or assessments are performed and after the aims, methods, anticipated benefits 
and potential hazards are explained.  The participant’s willingness to participate in the study 
will be documented in writing in a consent form, approved by the IRB, which will be signed 
by the participant and Investigator or designee with the date of signature indicated.  The 
Investigator will keep the original consent forms and copies will be given to the participants.  
It will also be explained to the participants that they are free to refuse entry into the study and 
free to withdraw from the study at any time without prejudice to future treatment.  Written 
and/or oral information about the study in a language understandable to the participant will 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
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prohibited without written consent from MonoSol Rx LLC. 
Page 49 of 55 
 
 
be given to all participants.  HIPAA guidelines for confidentiality and the principles of 
medical ethics will be adhered to during the study.   
It is the Sponsor’s responsibility to submit, or to assign responsibility to submit, all informed 
consents and revisions to the appropriate regulatory authorities, when necessary. 
15.3. 
Delegation of Investigator Tasks 
The Investigator may delegate tasks as appropriate to individuals who are qualified by 
education, training and experience (and state licensure where relevant) to perform the 
delegated task, as described in the FDA Guidance for Industry on Investigator 
Responsibilities – Protecting the Rights, Safety, and Welfare of Study Subjects; October 
2009. 
15.4. 
Subject Confidentiality 
All laboratory specimens, evaluation forms, reports, video recordings, and other records that 
leave the clinical study site will be identified only by the study specific Subject Identification 
Number (SID) to maintain subject confidentiality. All records will be kept in a locked file 
cabinet. All computer entry and networking programs will be done using study specific SIDs 
only. Clinical information will not be released without written permission of the subject, 
except as necessary for monitoring by IRB, the FDA, the sponsor, or the sponsor’s designee. 
 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
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Page 50 of 55 
 
 
 
16. 
REFERENCES 
Belafsky, PC, Mouadeb DA, Rees CJ, Pryor JC, Postma GN, Allen J, Leonard RJ. Validity 
and reliability of the Eating Assessment Tool (EAT-10). Ann Otol Rhinol Laryngol, 2008. 
117(12):919-24. 
Caramia MD, Palmieri MG, Desiato MT, Iani C, Scalise A, Telera S, Bernardi G. 
Pharmacologic reversal of cortical hyperexcitability in patients with ALS. Neurology. 
2000;54(1):58-64. 
Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, et al. The ALSFRS-R: 
a revised ALS functional rating scale that incorporates assessments of respiratory function. 
BDNF ALS Study Group (Phase III). J Neurol Sci 1999;169(1-2):13-21. 
Cheah BC, Vucic S, Krishnan AV, Kiernan MC. Riluzole, neuroprotection and amyotrophic 
lateral sclerosis. Curr Med Chem 2010;17(18):1942-199. 
Chen L, Liu X, Tang L, Zhang N, Fan D. Long-Term Use of Riluzole Could Improve the 
Prognosis of Sporadic Amyotrophic Lateral Sclerosis Patients: A Real-World Cohort Study 
in China. Front Aging Neurosci. 2016;8:246. 
Covis Pharmaceuticals, Inc. Prescribing information for Rilutek® (riluzole) tablets. 04/2016. 
Crary MA, Carnaby-Mann GD, Groher ME. Initial psychometric assessment of a functional 
oral intake scale for dysphagia in stroke patients. Arch Phys Med Rehabil 2005;86:1516-
1520. 
Desiato MT, Palmieri MG, Giacomini P, Scalise A, Arciprete F, Caramia MD. The effect of 
riluzole in amyotrophic lateral sclerosis: a study with cortical stimulation. J Neurol Sci. 
1999;169(1-2):98-107.  
Eisen A, Kim S, Pant B. Amyotrophic lateral sclerosis (ALS): a phylogenetic disease of the 
corticomotoneuron? Muscle Nerve. 1992;15(2):219-224. 
Harikrishnareddy D, Misra S, Upadhyay S, Modi M, Medhi B. Roots to start research in 
amyotrophic lateral sclerosis: molecular pathways and novel therapeutics for future. Rev 
Neurosci. 2015;26(2):161-181. 
Jimonet P, Barreau M, Blanchard JC, Boireau A, Doble A, Laduron P, Lavayre J, Malgouris 
C, Piot O, Pratt J and others. Synthesis, anticonvulsant and neuroprotective activities of RP 
66055, a riluzole derivative. Bioorg Med Chem. 1994;2(8):793-798. 
Le Liboux A, Lefebvre P, Le Roux Y, Truffinet P, Aubeneau M, Kirkesseli S, Montay G. 
Single- and multiple-dose pharmacokinetics of riluzole in white subjects. J Clin Pharmacol. 
1997;37(9):820-827. 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is strictly 
prohibited without written consent from MonoSol Rx LLC. 
Page 51 of 55 
 
 
Le Liboux A, Cachia JP, Kirkesseli S, Gautier JY, Guimart C, Montay G, Peeters PA, Groen 
E, Jonkman JH, Wemer J. A comparison of the pharmacokinetics and tolerability of riluzole 
after repeat dose administration in healthy elderly and young volunteers. J Clin Pharmacol. 
1999;39(5):480-486. 
National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). 
v4.03: June 14, 2010 [Internet]. Available at 
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf) 
(17JUL26 accessed.) 
Riviere M, Meininger V, Zeisser P, Munsat T. An analysis of extended survival in patients 
with amyotrophic lateral sclerosis treated with riluzole. Arch Neurol. 1998;55(4):526-528.  
Rosenbek JC, Robbins JA, Roecker EB, Coyle JL, Wood JL. A penetration-aspiration scale. 
Dysphagia 1996;11(2):93-8. 
Sanofi-Aventis. Prescribing information for RILUTEK (riluzole) tablets. 2008. 
Sommer M, Tergau F, Wischer S, Reimers CD, Beuche W, Paulus W. Riluzole does not have 
an acute effect on motor thresholds and the intracortical excitability in amyotrophic lateral 
sclerosis. J Neurol. 1999;246 Suppl 3:III22-26.  
Stefan K, Kunesch E, Benecke R, Classen J. Effects of riluzole on cortical excitability in 
patients with amyotrophic lateral sclerosis. Ann Neurol. 2001;49(4):536-539. 
Stys PK. General mechanisms of axonal damage and its prevention. J Neurol Sci. 2005;233(1-2):3-
13. 
Stys PK. Sodium channel blockers as neuroprotectants in neuroinflammatory disease: a 
double-edged sword. Ann Neurol. 2007;62(1):3-5. 
Vucic S, Lin CS, Cheah BC, Murray J, Menon P, Krishnan AV, Kiernan MC. Riluzole exerts 
central and peripheral modulating effects in amyotrophic lateral sclerosis. Brain. 2013;136(Pt 
5):1361-1370. 
Watanabe H, Atsuta N, Nakamura R, Hirakawa A, Watanabe H, Ito M, Senda J, Katsuno M, 
Izumi Y, Morita M and others. Factors affecting longitudinal functional decline and survival 
in amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Frontotemporal Degener. 
2015;16(3-4):230-236. 
 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
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Page 52 of 55 
 
 
Appendix A 
ALS Functional Rating Scale – Revised1 
 
                                                 
 
1 Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: A revised ALS functional 
rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group 
(Phase III). J Neurol Sci 1999; 169(1-2): 13–21 
 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
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Page 53 of 55 
 
 
APPENDIX B 
Placement Diagram and Instructions for Use  
Riluzole Oral Soluble Film 
 
Placement Diagram 
 
 
 
Instructions for Use: 
1. Keep the Riluzole Oral Soluble Film in the foil pouch until ready for use and use it 
right way after it is taken out of the pouch. 
2. Make sure your hands are dry. 
3. Fold the pouch along the dotted line to expose the tear notch.  Tear or cut with 
scissors. 
4.  Put the Riluzole Oral Soluble Film on the center of the top surface of the tongue 
immediately after taking it out of the pouch and close the mouth.  It will dissolve in 
minutes.  Administration with liquid is not necessary. 
5. While the film is dissolving do not chew, talk, swallow the film, or move the film 
from placement. 
6. As the film dissolves swallow your saliva in the normal manner. 
Placement on the top surface 
(Dorsal Aspect of the 
Tongue): 
 
Riluzole Oral Soluble film is 
to be centered on the top 
surface of the tongue, along 
the midline, with the posterior 
edge of the film along the 
posterior edge of the tongue 
as illustrated by the Figure. 
 
Ensure film is completely 
adhered to the lingual surface. 
 
Note: Figure is for illustrative 
purposes and not drawn to 
scale. 
Figure: Placement of ROSF 50 mg on the top surface (dorsal aspect) of the tongue. 
Film 
Dorsal aspect of 
the tongue 
Lip 
Lip 
Posterior edge 
of the tongue 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
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APPENDIX C 
Eating Assessment Tool2 (EAT-10) 
 
Please answer each of the ten questions listed below by circling the appropriate number that 
you feel best describes how you feel, with:  0= no problem at all; 4= severe problems. 
 
 
Circle the appropriate response: 
To what extent are the following scenarios problematic for you? 
0= No Problem  
4=Severe Problem  
1. My swallowing problem has caused me to lose weight. 
0 
1 
2 
3 
4 
2. My swallowing problem interferes with my ability to go out for meals. 
0 
1 
2 
3 
4 
3. Swallowing liquid takes extra effort. 
0 
1 
2 
3 
4 
4. Swallowing solids takes extra effort. 
0 
1 
2 
3 
4 
5. Swallowing pills takes extra effort. 
0 
1 
2 
3 
4 
6. Swallowing in painful. 
0 
1 
2 
3 
4 
7. The pleasure of eating is affected by my swallowing. 
0 
1 
2 
3 
4 
8. When I swallow food sticks in my throat. 
0 
1 
2 
3 
4 
9. I cough when I eat.  
0 
1 
2 
3 
4 
10. Swallowing is stressful. 
0 
1 
2 
3 
4 
                                                                                                                                        Total EAT-10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                 
 
2 Belafsky PC, Mouadeb DA, Rees CJ, Pryor JC, Postma GN, Allen J, and Leonard RJ. Validity and reliability 
of the Eating Assessment Tool (EAT-10). Ann Otol Rhinol Laryngol 117: 919-924, 2008. 


Protocol Number: 17MO1R-0012  Swallowing Safety in ALS 
Version No 2.0, October 18, 2017 
Riluzole Oral Soluble Film 
 
 
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APPENDIX D 
 
Functional Oral Intake Scale (FOIS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
NCT03679975
A Single Center Study to Evaluate the Effect of Riluzole Oral Soluble Film on 
Swallowing Safety in Individuals With Amyotrophic Lateral Sclerosis
Statistical Analysis Plan for Study 17MO1R-0012,  12-Oct-2018


STATISTICAL ANALYSIS PLAN 
Aquestive Therapeutics 
Protocol 17MO1R-0012, Amendment I 
Version: 1.0, 12Oct2018 
Confidential
SOP-STAT-005-AD-02-01 
Page 1 of 17     STATISTICAL ANALYSIS PLAN 
STATISTICAL ANALYSIS PLAN 
Sponsor: 
Aquestive Therapeutics 
30 Technology Drive 
Warren, NJ 07059 
USA 
 A Single Center Study to Evaluate the Effect of Riluzole Oral Soluble Film on 
Swallowing Safety in Individuals With Amyotrophic Lateral Sclerosis
Protocol No: 17MO1R-0012 
Final Version: 1.0 
Date: 12-Oct-2018 
Prepared by: 
Sudheer Ravula 
inVentiv Health Clinical 
This document contains confidential information of Aquestive Therapeutics.  Any viewing or disclosure of 
such information that is not authorized in writing by Aquestive Therapeutics is strictly prohibited.  Such 
information may be used solely for the purpose of reviewing or performing this study.  
NCT03679975


inVentiv 
Health 
STATISTICAL ANALYSIS PLAN 
Aquestive Therapeutics 
Protocol 17M01 R-0012, Amendment I 
Version: 1.0, 120ct2018 
Approval 
Sponsor: 
Aquestive Therapeutics 
30 Technology Drive 
Warren, NJ 07059 
USA 
A Single Center Study to Evaluate the Effect of Riluzole Oral Soluble Film on 
Swallowing Safety in Individuals With Amyotrophic Lateral Sclerosis 
Protocol No: 17M01R-0012, Amendment I 
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Allen H. Heller, MD MPH 
Approval Date 
Principal, Pharma Study Design, LLC 
Consultant to Aquestive Therapeutics 
Carla Buan 
Product Development Manager 
Aquestive Therapeutics 
in Ventiv Health 
SOP-STAT-005-AD-02-01 
Approval Date 
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Approval Date 
Confidential 
Page 2 of 17 


 
 
STATISTICAL ANALYSIS PLAN 
Aquestive Therapeutics 
Protocol 17MO1R-0012, Amendment I 
Version: 1.0, 12Oct2018 
 
 
Confidential 
 
SOP-STAT-005-AD-02-01 
 
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TABLE OF CONTENTS  
 
TABLE OF CONTENTS ................................................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................................4 
1. 
INTRODUCTION .............................................................................................................................5 
2. 
STUDY OBJECTIVE .......................................................................................................................6 
3. 
STUDY DESIGN ..............................................................................................................................7 
3.1 
General Design ................................................................................................................................7 
3.2 
Treatment description ......................................................................................................................7 
4. 
SCHEDULE OF ACTIVITIES .........................................................................................................8 
5. 
ANALYSIS POPULATION .............................................................................................................9 
5.1 
Safety Population .............................................................................................................................9 
6. 
STATISTICAL METHODOLOGY ................................................................................................ 10 
6.1 
Statistical and Analytical Issues..................................................................................................... 10 
6.1.1 
Statistical Methods ............................................................................................................. 10 
6.1.2 
Handling of Dropouts and Missing Data ........................................................................... 10 
6.1.3 
Pooling of Investigative Sites ............................................................................................ 10 
6.2 
Determination of Sample Size ....................................................................................................... 10 
6.3 
Subject Characteristics ................................................................................................................... 10 
6.3.1 
Subject Disposition ............................................................................................................ 10 
6.3.2 
Protocol Deviations ............................................................................................................ 11 
6.3.3 
Background and Demographic Characteristics .................................................................. 11 
6.3.4 
Study Drug Administration ................................................................................................ 11 
6.3.5 
Prior and Concomitant Medications and Therapies ........................................................... 11 
6.3.6 
Medical Histories ............................................................................................................... 12 
6.4 
Efficacy Analysis ........................................................................................................................... 12 
6.5 
Safety Analysis .............................................................................................................................. 12 
6.5.1 
Adverse Events .................................................................................................................. 12 
6.5.2 
Physical and Neurological Examination ............................................................................ 13 
6.5.3 
Vital Signs ......................................................................................................................... 13 
6.5.4 
Laboratory Parameters ....................................................................................................... 14 
6.5.5 
ALS Functional Rating Scale – Revised (ALSFRS-R) ...................................................... 14 
6.5.6 
Functional Oral Intake Scale – FOIS ................................................................................. 14 
6.5.7 
Eating Assessment Tool 10 – (EAT-10) ............................................................................ 15 
6.5.8 
Statistical Analyses ............................................................................................................ 15 
6.6 
Changes to Methods Planned in the Protocol ................................................................................ 16 
7. 
REFERENCES ................................................................................................................................ 17 
 
 
 
 


 
 
STATISTICAL ANALYSIS PLAN 
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Protocol 17MO1R-0012, Amendment I 
Version: 1.0, 12Oct2018 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE 
Adverse Event 
ALS 
Amyotrophic Lateral Sclerosis 
ALSFRS-R 
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
EAT 
Eating Assessment Tool 
FDA 
Food and Drug Administration 
FOIS 
Functional Oral Intake Scale 
H 
Above Normal Range 
HR 
Heart Rate 
ICF 
Informed Consent Form 
L 
Below Normal Range 
Max 
Maximum (equivalent to Max.) 
MedDRA® 
Medical Dictionary For Regulatory Activities 
Mg 
Milligram 
Min 
Minimum (equivalent to Min.) 
N 
Number of observations 
PAS 
Penetration Aspiration Scale 
PT 
MedDRA® Preferred Term 
ROSF 
Riluzole Oral Soluble Film 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System 
SD 
Standard Deviation 
SOC 
MedDRA® System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-Emergent Adverse Event 
VFSS 
Videofluoroscopic Swallowing Study 
WHO DD 
World Health Organization Drug Dictionary 
 
 
 


 
 
STATISTICAL ANALYSIS PLAN 
Aquestive Therapeutics 
Protocol 17MO1R-0012, Amendment I 
Version: 1.0, 12Oct2018 
 
 
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1. INTRODUCTION 
This statistical analysis plan (SAP) is intended to give a detailed description of the summaries 
and the analyses that will be generated for the present study by inVentiv Health Clinical. 
Analyses specified in this plan are based on Protocol 17MO1R-0012 Version 2.0, Amendment I, 
dated 18 October 2017. Safety and tolerability analyses will be described.  
 
The original plan has changed as described below. Further details are documented in the 
remainder of this document. These changes will also be described in the clinical study report 
(CSR). 
  
Top-line clinical results from the Videofluoroscopic Swallowing Study (VFSS) for the first 7 
completed patients were presented to the Food and Drug Administration (FDA) on Sept 10 2018.  
At that time, two additional patients had been enrolled but had not yet undergone the VFSS.  On 
Sept 12 2018, the FDA agreed with the Sponsor that due to the lack of any signal of detrimental 
effect on VFSS after one dose of study drug, the study would be terminated after the completion 
of 9 patients (the seven completed by Sept 10 and the two additional patients in screening at that 
time).  In addition to the lack of signal of any harmful effect, the Agency and the Sponsor took 
into account the difficulty and hardship involved for these disabled patients in participating in the 
study, the potential risks of participation (including possible reaction to barium, potential for 
aspiration, and exposure to radiation), and the fact that the participating patients would derive no 
direct benefit for participation.  
 
When applicable, all methodology and related processes will be conducted according to Standard 
Operating Procedures (SOPs) of InVentiv Health Clinical.  
 
 


 
 
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2. STUDY OBJECTIVE 
The objective is to evaluate the effect, if any, of a single 50 mg dose of Riluzole Oral Soluble 
Film (ROSF) on swallowing safety in individuals with amyotrophic lateral sclerosis.  
 
 
 


 
 
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3. STUDY DESIGN  
3.1 General Design 
This is a single site, phase 2, single dose, open-label safety study to evaluate the effect of 
Riluzole Oral Soluble Film (ROSF) on swallowing safety in individuals with Amyotrophic 
Lateral Sclerosis (ALS). The original plan called for approximately 30 subjects with ALS to be 
enrolled, with a goal of 25 completed subjects after allowance for dropouts. These subjects were 
to undergo a clinical evaluation including the validated Amyotrophic Lateral Sclerosis 
Functional Rating Scale-Revised (ALSFRS-R). Swallowing safety will be assessed using the 
gold standard Videofluoroscopic Swallowing Study (VFSS) to afford direct visualization of the 
swallowing process and any episodes of penetration or aspiration will be quantified using the 
validated Penetration Aspiration Scale (PAS). Subjects will undergo a standardized protocol that 
includes 11 bolus stimuli presentations of different liquid and food materials to test the swallow 
across a continuum of textures and materials. Immediately following this, subjects will be given 
a single dose of ROSF 50 mg, placed on the median lingual sulcus of the dorsum of the tongue. 
Three minutes after the administration of ROSF, the identical standardized VFSS protocol will 
be re-administered to allow a comparison of swallowing safety (using the PAS scale) pre vs. post 
ROSF administration.  
 
The study visit duration is expected to be approximately 30 days from time of screening to 
completion of study. 
 
3.2 Treatment description 
A single dose of 50 mg Riluzole Oral Soluble Film (ROSF) will be administered to the subject, 
placed on the median lingual sulcus of the dorsum of the tongue. The treatment administered in 
this study is presented in Table 3-1 
Table 3-1 Treatment Description  
Treatment 
Description 
Riluzole 50 mg Oral 
Soluble Film 
1 x 50 mg Riluzole Oral Soluble Film 
This is an open-label study and neither subjects nor clinic staff will be blinded. 
 
 


 
 
STATISTICAL ANALYSIS PLAN 
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4. SCHEDULE OF ACTIVITIES 
Evaluation 
Screening 
Visit 1 
Written Informed Consent  
X 
 
Inclusion/Exclusion Review 
X 
Xa 
Documentation of Disease 
X 
 
Record/Review Concomitant Medications 
X 
Xa 
Medical History/ Demographics 
X 
 
Height and Weight 
X 
 
Vital Signs – HR, BP, RR  
 
Xb 
Vital Signs – HR, BP, RR and temperature 
X 
Xa 
Comprehensive Physical Exam 
X 
 
Brief Physical Exam 
 
Xb 
Neurological Examination 
X 
 
Brief Neurological Exam 
 
Xb 
Eating Assessment Tool-10 (EAT-10) 
X 
Xa 
Functional Oral Intake Scale (FOIS) 
X 
Xa 
ALS Functional Rating Scale - Revised (ALSFRS-R) 
X 
Xa 
Oral Examination  
X 
Xc 
VFSS 1 - Penetration-Aspiration Scale (pre-dose) 
 
X 
VFSS 2 - Penetration-Aspiration Scale (post-dose) 
 
X 
Clinical laboratory evaluation(s) (hematology, chemistry, 
urinalysis)d 
X 
Xb 
Urine Pregnancy Test (females of childbearing potential) 
X 
Xa 
Adverse Event 
X 
Xc 
Dispense Study Drug (one dose)  
 
X 
aBefore VFSS 1 procedure 
bAfter VFSS 2 procedure 
cBoth – before VFSS 1 procedure and after VFSS 2 procedure 
dSee Section 6.5.4 Laboratory Parameters 
 
 
 
 
 


 
 
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5. ANALYSIS POPULATION 
The analysis of safety parameters will be based on the safety population detailed in Section 5.1 
below. 
 
5.1 Safety Population  
The safety population is defined as the group of subjects who receive the study medication. 
 
 
 


 
 
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6. STATISTICAL METHODOLOGY 
6.1 Statistical and Analytical Issues 
6.1.1 Statistical Methods 
Percentages and Decimal Places 
If not otherwise specified, the following rules are applied, with the exception of listings: 
 Percentages will be presented to 1 decimal point. 
 Percentages equal to 0 or 100 will be presented as such without a decimal point. 
 Minimum and maximum will be presented with the same precision as the original values 
and, mean, standard deviation, and median will be presented with one more decimal place 
than the original values. 
 
Software to be used for Analysis 
The inferential statistical analyses, the safety data tables and listings will be created using SAS®, 
software version 9.4 or higher. 
 
6.1.2 Handling of Dropouts and Missing Data 
Missing values will not be imputed. The shifts required for the shift tables will already be 
included in the ADaM dataset. 
 
6.1.3 Pooling of Investigative Sites 
Pooling of investigative sites is not applicable for this study. 
 
6.2 Determination of Sample Size 
The original protocol specified that approximately thirty (30) subjects with ALS would be 
recruited to obtain a final sample size of at least 25 completed. As previously noted, the Sponsor 
and FDA have agreed to terminate the study with a completed sample size of 9 subjects. 
 
6.3 Subject Characteristics 
6.3.1 Subject Disposition 
Subject disposition will be summarized as number and percentage of subjects in the treatment 
group for the below listed categories. 
 Screened and screen failure subjects 
 Enrolled and not enrolled subjects 
 Dosed and not dosed subjects 
 Number of subjects completed the study  
 Number of subjects discontinued with reason 
 
Subject disposition information will be listed. In addition, subjects who did not complete the 
VFSS will also be presented in this listing, including early termination reason and date and time 
of discontinuation. 
 


 
 
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For subjects enrolled, not enrolled and screen failures, the percentage denominator will be the 
number of screened subjects. For all other calculations, the percentage denominator will be the 
number of subjects dosed (safety population). 
 
6.3.2 Protocol Deviations 
All protocol deviations will be collected on CRF and will be listed by subject including start 
date, end date and impact of deviation. Study day will be presented along with start and end date 
of deviation. 
 
6.3.3 Background and Demographic Characteristics 
Descriptive statistics (sample size, mean, median, standard deviation [SD], minimum [Min] and 
maximum [Max]) will be presented for continuous variables: age, height, weight and body mass 
index [BMI]. Frequency counts and percentages will be tabulated for categorical variables: age 
group (<18, 18-40, 41-65, and > 65 years), gender, ethnicity, and race.  
 
Results will be presented for the safety population.  
 
All demographic characteristics will be listed by subject. 
 
6.3.4 Study Drug Administration 
The study drug administration details (start/end date, start/end time) will be listed by subject. The 
dosing time will be set to the time the film is placed on the center of the top surface of the 
tongue. The total time taken for complete dissolution of film will be recorded in seconds and 
listed by subject. 
 
6.3.5 Prior and Concomitant Medications and Therapies 
The World Health Organization Drug Enhanced (WHO DDE) Version Jun2016, format B2 will 
be used to classify all medications reported during the study to an Anatomical Therapeutic 
Chemical (ATC) Level 1 term and a standardized medication name. 
 
Prior medication is any medication/therapy stopped prior to the study drug administration, 
regardless of medication start date. Concomitant medication is any medication started and not 
stopped before the study drug administration. 
 
Concomitant Medications will be summarized by Anatomical Therapeutic Chemical (ATC) 
category Level 1 and by standardized medication name. ATC Level 1 categories and 
standardized medication names will appear in an alphabetical order on the summary table. For 
each medication, the number of subjects and percentages will be displayed. 
 
The use of prior and/or concomitant medication will be listed by subject. 
 


 
 
STATISTICAL ANALYSIS PLAN 
Aquestive Therapeutics 
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6.3.6 Medical Histories 
Medical history will be collected at screening and reviewed for any exclusionary criteria. The 
Medical Dictionary for Regulatory Activities (MedDRA®) Version 19.1 will be used to classify 
all medical history findings to a System Organ Class (SOC) and Preferred Term (PT). 
 
All medical history data will be listed and sorted by subject and alphabetically according to SOC 
and PT 
 
 
6.4 Efficacy Analysis 
No efficacy analysis is planned as per the protocol. This is a single dose safety study with no 
measurement of efficacy. 
 
6.5 Safety Analysis 
Safety data will be evaluated through the assessment of PAS scores on the VFSS, adverse events 
(AEs), clinical signs and symptoms from physical and neurological examination following study 
drug administration, and vital signs assessments. Treatment-Emergent Adverse Events (TEAEs), 
and vital signs, will be summarized. No inferential analysis will be carried out for the safety data. 
 
Shells for all tables and listing referred to in this section are displayed in separate document. 
 
6.5.1 Adverse Events 
Treatment-emergent AE (TEAE)s will be defined as AEs that occur on or after the date and time 
of study drug administration, or those that first occur pre-dose but worsen in frequency or 
severity after study drug administration. TEAEs will be captured through the end of the study. 
TEAEs and non-TEAEs (those occurring prior to administration of study medication or that first 
occurred prior to study drug administration and did not worsen in frequency or severity) will be 
listed. 
 
The MedDRA® dictionary version 19.1 will be used to classify all AEs reported during the study 
by SOC and PT.  
The relationship of TEAEs to study drug will be classified according to the study protocol as 
unrelated, unlikely, possible, or probable. The severity of AEs will be rated according to the 
study protocol as: mild, moderate, or severe. 
An SAE is any untoward medical occurrence that: 
- results in death, 
- is life-threatening, 
- requires inpatient hospitalization or prolongation of existing hospitalization, 
- results in persistent or significant disability/incapacity, 


 
 
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- is a congenital anomaly/birth defect 
A significant AE will be defined as any event (other than those reported as serious) that 
necessitated an intervention, including withdrawal of treatment, or significant additional 
concomitant therapy. 
Serious and significant AEs will be listed separately. 
6.5.2 Physical and Neurological Examination 
Subjects will undergo a comprehensive physical and neurological examination at screening, and 
a brief physical and neurological examination at Visit 1 following the second VFSS.   
The comprehensive physical examination will include complete vital signs, weight, height, 
general appearance, and evaluation of systems: head, ears, eyes, nose, and throat; respiratory; 
abdomen; lymph nodes; spine; skin; cardiovascular; and extremities.  The brief general physical 
examination will include abbreviated vital signs (blood pressure, heart rate, respiratory rate), and 
examination of the cardiovascular and respiratory systems and abdomen. Other elements may be 
included depending on symptoms or physical findings. 
The comprehensive neurological examination will include (as permitted by the patient’s 
capabilities) cranial nerves 2-12, muscle tone and strength, tendon reflexes and plantar response, 
sensory function (pain, light touch, position, vibration), coordination (finger-nose), and gait.  The 
brief neurological examination will include cranial nerves 2-12, muscle strength, tendon reflexes, 
plantar response, and sensory function (pain, light touch, position, vibration). Other elements 
may be included depending on symptoms or physical findings. 
Physical and neurological examination data will be listed separately by subject. 
Any abnormal findings judged to be clinically significant will be documented as medical history 
or as an AE, depending upon whether noted at screening, prior to dosing or after dosing, as 
appropriate. Any physical examination or neurological examination findings documented as AEs 
will be included in the AE summaries. 
 
6.5.3 Vital Signs 
Complete vital sign measurements (blood pressure, heart rate, respiratory rate and temperature) 
will be performed at screening, and at Visit 1 pre-VFSS 1. The abbreviated vital sign 
measurements (blood pressure, heart rate, and respiratory rate) will be performed at Visit 1 post-
VFSS 2.  
 
 
Descriptive statistics (sample size, mean, median, SD, Min and Max,) for each vital sign 
parameter will be presented for screening, pre-VFSS 1, and post-VFSS 2. Unscheduled 
timepoints will be included in the listings but not in the summary tables except for baseline 
calculation if applicable. Descriptive statistics for change from baseline for post-VFSS 2 will 
also be presented. Baseline will be defined as the last non-missing result (scheduled or 
unscheduled) obtained prior to study drug administration. Results from post-dose repeat tests 
will not be included in the summary statistics unless the repeat was required (and documented as 
such) due to technical reasons or an invalid initial result.  


 
 
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A listing of all vital signs results will be provided. 
 
6.5.4 Laboratory Parameters 
Clinical laboratory (hematology, serum chemistry, and urinalysis) results will be obtained at 
screening and at early termination or end of study (post-VFSS 2). 
 
 
Serum chemistry parameters include the following: alanine aminotransferase (ALT), albumin, 
aspartate aminotransferase (AST), urea, chloride, creatinine, creatinine kinase, potassium, 
sodium, bicarbonate, magnesium, bilirubin, and serum pregnancy test. 
 
Hematology parameters include the following: hematocrit, hemoglobin, platelet count, red blood 
cell count, red blood cell indices (mean corpuscular volume [MCV], mean corpuscular 
hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC]), neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, and white blood cell count with differential.  
 
Urinalysis parameters include the following: color and clarity, pH, specific gravity, protein, 
glucose, ketones, bilirubin, occult blood, nitrite, urobilinogen, leukocytes, and urine pregnancy 
test. Unless otherwise specified, microscopic examination will be performed on abnormal 
finding. 
 
Listings of all clinical laboratory results will be provided with the abnormal values flagged with 
"L" for low and "H" for high for continuous parameters, and “A” for abnormal for categorical 
parameters.  
 
 
6.5.5 ALS Functional Rating Scale – Revised (ALSFRS-R) 
The ALSFRS-R is a quickly administered (5 minute) ordinal rating scale (ratings 0-4) used to 
determine subjects’ assessment of their capability and independence in 12 functional 
activities/questions performed at screening, and at Visit 1 pre-VFSS 1. All 12 activities are 
relevant in ALS. 
 
Descriptive statistics (sample size, median, Min and Max,) will be presented for screening, and at 
Visit 1 pre-VFSS 1 as appropriate. 
A listing of ALSFRS-R results will also be provided, as an overall score, as individual question 
scores, and by individual functional domains. 
6.5.6 Functional Oral Intake Scale – FOIS 
The FOIS is a simple 7 point scale that describes the subject’s functional status with respect to 
oral intake, ranging from 1 (No oral intake) to 7 (Total oral intake with no restrictions), and will 
be administered at Screening, and at Visit 1 pre-VFSS 1. 
 


 
 
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Number and percentage of subjects will be presented for each point on the scale for screening, 
and for Visit 1 pre-VFSS 1 as appropriate. 
 
A listing of FOIS results will also be provided. 
6.5.7 Eating Assessment Tool 10 – (EAT-10) 
The Eating Assessment Tool-10, is a validated 10-item patient report scale of perceived 
swallowing impairment, and will be administered at Screening, and at Visit 1 pre-VFSS 1. The 
EAT-10 uses a 5-point ordinal rating scale where a patient rates their perceived degree of 
impairment for each item from 0 (no impairment) to 4 (severe impairment) for a total range of 
scores between 0 (no perceived swallowing impairment) to 40 (severe impairment). 
Descriptive statistics (sample size, median, Min and Max,) will be presented for screening, and 
for Visit 1 pre-VFSS 1 as appropriate. 
A listing of EAT-10 results will also be provided.  
6.5.8 Statistical Analyses 
The primary objective is to assess the effect of the ROSF formulation, if any, of a single 50 mg 
dose of ROSF on swallowing safety in subjects with ALS. The analyses will be descriptive only, 
and not hypothesis-testing. 
The PAS scores obtained in swallow tests during VFSS 1-PAS (before ROSF) and VFSS 2-PAS 
(after ROSF) will be compared within each subject and across subjects.  
Swallowing Evaluation Results: 
There is considerable discussion in the literature regarding the psychometric properties and 
optimal/correct ways to analyze PAS scores (an 8-point ordinal scale, where higher scores 
indicate lower function, measured individually for 11 swallowing trials). There is no method 
universally accepted as best due to the psychometric and clinical characteristics of the PAS. The 
three methods described below will be used to present the results of this study. This approach 
was determined post hoc, at the time of examining results for the first seven patients. 
“Single worst score” method: 
A number of publications use the single worst score on any swallowing trial as an indicator of 
PAS swallowing function.  Results presented will include the number/percentage of patients who 
stay the same, increase or decrease (and by how many points). 
“Sum of scores” method: 
The sum of 11 PAS scores will be used.  Results presented will include the number/percentage of 
patients who stay the same, increase or decrease sum (and by how much). 
 
“Steele 4-category” method: 
Steele and associates (Dysphagia 2017) propose categorization of single worst PAS score into 4 
categories.  Steele A includes scores 1, 2, 4; Steele B includes 3, 5, 6; Steele C includes a score 


 
 
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of 7 and Steele D includes a worst score of 8. Results presented will include the 
number/percentage of patients who stay the same, increase or decrease (and by how much). 
Interim Analyses: 
An unofficial interim analysis was performed after 7 patients had completed the study.  As 
previously mentioned, these results were discussed with the FDA and they agreed with the 
Sponsor that the study should be terminated after the two additional patients who had been 
screened but not yet completed were evaluated with the VFSS. 
6.6 Changes to Methods Planned in the Protocol  
See previous sections regarding methods changed since the protocol. 
Based upon FDA feedback Exclusion criteria #2 will be updated to the following:  
Subjects with a prior swallowing study that has shown a PAS score of 4 or greater and subjects 
with a PAS score of 3 or greater and who have exceeded more than 2 abnormal swallows (PAS 
of 3 or greater) will be excluded from participation in the study. 
 
Videofluoroscopic Swallowing Study (VFSS1 - PAS): 
 
The 12th bolus was inadvertently included as part of the PAS evaluation. This bolus is typically 
included only to determine if the subject can open the mouth to the diameter of the pill. The PAS 
is not normally assessed during this bolus; therefore, the 12th bolus trial presentation at the end 
of the list will be removed from the study and the section 10.2.2. in protocol is clarified as 
follows:  
After consent has been verified and screens completed, the patient will be seated and will 
complete a standardized bolus protocol that includes 11 bolus trial presentations.  
 
 


 
 
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7. REFERENCES 
1. Chuang-Stein C. Summarizing laboratory data with different reference ranges in multi-
center clinical trials. Drug Information Journal. 1992; 26:77-84. 
2. Karvanen J. The statistical basis of laboratory data normalization. Drug Information 
Journal. 2003; 37:101-107.