Conditions: Amyotrophic Lateral Sclerosis
Keywords: bulbar dysfunction
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 28
Healthy volunteers: no

Brief summary:
Nuedexta is FDA approved for the treatment of pseudobulbar affect in ALS patients and anecdotal reports of improvements in speech, salivation or swallowing have been reported. However, no prospective study has been conducted to comprehensively examine and determine the physiologic impact of Nuedexta on both speech and swallowing physiology in a large group of ALS individuals. These data are needed in order to provide evidence-based guidance to the management of bulbar dysfunction in ALS.

Detailed description:
Although advances in the management of bulbar dysfunction in ALS have been disappointing, recent interest has surfaced regarding the therapeutic potential of a pharmaceutical agent, Nuedexta (dextromethorphan HBr and quinidine sulfate), for the treatment of bulbar symptomology in individuals with ALS. Although Nuedexta received approval from the Food and Drug Administration (FDA) to target symptoms of pseudobulbar affect (PBA) in ALS; anecdotal reports of improvements in speech, salivation or swallowing were reported from Neurologists treating ALS individuals who were administered Nuedexta. Subsequently, a Phase II clinical trial was conducted that reported improvements in speech, swallowing and salivation following 30-days of Nuedexta treatment. One serious limitation of this study, however, is the fact that the primary outcome employed was a perceptual patient-report scale (PRO) (Center for Neurological Study Bulbar Function Scale, CNS-BFS), with no objective physiologic outcomes to confirm actual change in bulbar physiology. The absence of any objective clinical physiologic outcomes is particularly important when examining effects of Nuedexta, given that it contains selective serotonin reuptake inhibitors (SSRIs), or serotonergic antidepressants, that can impact the regulation of emotional expression, feelings of wellbeing and modulation of depression (all known to impact the response an individual will provide on a PRO measure). Furthermore, findings based on PRO's must be validated with studies that utilize objective physiologic outcomes of speech and swallowing function. Great excitement exists regarding the potential impact of Nuedexta on bulbar function in ALS with many neurologists prescribing Nuedexta to treat these symptoms in ALS patients. To date, however; no data exists to examine and determine the physiologic impact of Nuedexta on speech or swallowing physiology. These data are needed in order to validate the initial patient-reported outcomes of the Phase II clinical trial and to provide evidence-based guidance to the management of bulbar dysfunction in ALS.

Arms:
arm 1: Participants enrolled in this group will be prescribed dextromethorphan HBr and quinidine sulfate (Nuedexta) as recommended by their treating neurologist. 20 mg dextromethorphan HBr and 10mg quinidine sulfate will be administered orally with 1 capsule every day for the initial 7 days followed by 1 capsule every 12 hours for the remaining 23 days of the study. Participants will be evaluated 30 days apart to determine the impact of treatment.

Interventions: intervention 1: dextromethorphan HBr and quinidine sulfate
Intervention descriptions: intervention 1: All eligible and enrolled study participants will be administered the study drug, Nuedexta, as recommended by their treating neurologists.The drug will be administered per the efficacy and safety protocol, with no changes in administration method or recommended dose for individuals with ALS. Prior to commencing treatment with Nuedexta, participants will undergo a comprehensive bulbar evaluation of swallowing, airway protection, speech functions, and complete validated patient-reported surveys. Following 30 days of Nuedexta treatment, participants will be e-evaluated using the same battery of assessments.

Protocol document:
Prot_SAP_000.pdf: 
Page 1 of 14 
Protocol Version 2.0 
 
 
8/1/2019 
 
 
 
 
Impact of Nuedexta on Bulbar Physiology and Function in ALS 
 
NCT03883581 
 
Study Protocol 
 
 
 


Page 2 of 14 
Protocol Version 2.0 
 
 
8/1/2019 
 
 
FULL PROTOCOL TITLE 
Impact of Nuedexta on Bulbar Physiology and Function in ALS 
 
Protocol Version: 2.0 
Protocol Date: 08/01/2019 
 
 
 
 
 
Protocol Principal Investigators (PPI): 
Lauren Tabor-Gray, PhD, CCC-SLP 
Department of Neurology 
Phil Smith Neuroscience Institute 
Holy Cross Hospital 
Fort Lauderdale, FL 33308 
Email: lauren.tabor@holy-cross.com 
 
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@ufl.edu 
 
 
 
Study Intervention Provided by: 
ALS Association Clinical Management Grant  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 3 of 14 
Protocol Version 2.0 
 
 
8/1/2019 
 
Impact of Nuedexta on Bulbar Physiology and Function in ALS. 
SIGNIFICANCE. 
Progressive degeneration of bulbar musculature results in dysphagia (swallowing impairment) and dysarthria 
(speech impairment) in individuals with ALS.  Regardless of disease onset type, bulbar dysfunction impacts 85% 
of ALS individuals at some point in the disease course (Carpenter et al., 1977) with patients rating the inability 
to communicate or eat as the worst symptoms of the disease (Paganoni et al., 2015).  Bulbar dysfunction 
contributes to malnutrition, social isolation, increased caregiver burden, compromised pulmonary function, and 
increased mortality in ALS (Boitano, 2006; Bouteloup et al., 2009; Tabor et al., 2016).  Despite these devastating 
sequelae, advances in treatment are lacking and primarily consists of a palliative symptom management 
approach including diet and environmental modifications, feeding tube placement and alternative communication 
strategies, which are incorporated in a reactive manner following identification of impairments (Miller et al., 2009).  
The lack of targeted treatment options to proactively improve or maintain bulbar function represents a crucial 
clinical management gap in the care of individuals with ALS (Kühnlein et al., 2008; Plowman et al., 2017). 
Currently there exist no efficacious treatments to proactively prolong safe and efficient oral intake, or 
extend functional communication.  
 
Although advances in the management of bulbar dysfunction in ALS have been disappointing, recent interest 
has surfaced regarding the therapeutic potential of a pharmaceutical agent, Nuedexta (dextromethorphan HBr 
and quinidine sulfate), for the treatment of bulbar symptomology in individuals with ALS.  Although Nuedexta 
received approval from the Food and Drug Administration (FDA) to target symptoms of pseudobulbar affect 
(PBA) in ALS; anecdotal reports of improvements in speech, salivation or swallowing were reported from 
Neurologists treating ALS individuals who were administered Nuedexta (Smith, personal report). Subsequently, 
a Phase II clinical trial was conducted that reported improvements in speech, swallowing and salivation following 
30-days of Nuedexta treatment (Smith et al., 2017). One serious limitation of this study, however, is the fact that 
the primary outcome employed was a perceptual patient-report scale (PRO) (Center for Neurological Study 
Bulbar Function Scale, CNS-BFS), with no objective physiologic outcomes to confirm actual change in bulbar 
physiology. The absence of  any objective clinical physiologic outcomes is particularly important when examining 
effects of Nuedexta, given that it contains selective serotonin reuptake inhibitors (SSRIs), or serotonergic 
antidepressants, that can impact the regulation of emotional expression, feelings of wellbeing and modulation of 
depression (all known to impact the response an individual will provide on a PRO measure). Furthermore, 
findings based on PRO’s must be validated with studies that utilize objective physiologic outcomes of speech 
and swallowing function. Great excitement exists regarding the potential impact of Nuedexta on bulbar function 
in ALS with many neurologists prescribing Nuedexta to treat these symptoms in ALS patients. To date, however; 
no data exists to examine and determine the physiologic impact of Nuedexta on speech or swallowing 
physiology. These data are needed in order to validate the initial patient-reported outcomes of the Phase II 
clinical trial (Smith et al., 2017) and to provide evidence-based guidance to the management of bulbar 
dysfunction in ALS.  
 
Therefore, the primary goal of this proposal is to rigorously evaluate the impact of a pharmacological treatment, 
Nuedexta, on bulbar function in individuals with ALS.  The central supposition is that functions of swallowing, 
airway protection and communication will improve following 30-days of Nuedexta treatment.  The following 
specific aims will test this premise: 
 
Aim 1. Determine the effect of Nuedexta on swallowing physiology and airway defense physiologic 
capacity in ALS.  
Hypotheses: Following 30-days of Nuedexta treatment, ALS individuals will demonstrate: 
(1) Improved global swallowing function as indexed by lower total DIGEST scores 
(2) Improved swallowing safety as indexed by lower penetration-aspiration scores 
(3) Improved swallowing efficiency as indexed by lower normalized residue ratio scale scores 
(4) Improved airway defense physiologic capacity as indexed by increased expiratory cough flow velocity. 
 
Aim 2. Determine the effect of Nuedexta on speech intelligibility, speaking rate and communicative 
efficiency in ALS.  
Hypothesis: ALS individuals will demonstrate increased speech intelligibility, speaking rate and communicative 
efficiency on the sentence intelligibility test following 30-days of Nuedexta treatment. 


Page 4 of 14 
Protocol Version 2.0 
 
 
8/1/2019 
 
Aim 3. Determine the impact of Nuedexta on patient-perceived swallowing function, communication 
effectiveness, and disease severity and progression. 
Hypothesis: Following 30-days of Nuedexta treatment, ALS individuals will report improvements on validated, 
patient-reported measures of swallowing (Eating Assessment Tool-10); communication (Communication 
Participation Item Bank-10 survey); bulbar function (Center for Neurological Study-Bulbar Function Scale) and 
overall disease severity (ALS Functional Rating Scale-Revised). 
 
SUPPORTING PRELIMINARY DATA. 
We recently completed a randomized sham-controlled trial to investigate the impact of expiratory muscle strength 
training (EMST) on respiratory and bulbar function in ALS (Plowman et al., 2018). Three individuals enrolled in 
this trial were also taking Nuedexta.  Upon stratification of data following completion of this clinical trial was the 
finding that patients who were also on Nuedexta treatment (n=3) demonstrated superior gains to those 
completing EMST alone. An example of one such participant’s cough spirometry data is depicted below and 
demonstrates that their airway defense capabilities to expel secretions or tracheal aspirate significantly improved 
(Figure 1).  Specifically, cough volume acceleration increased by 570%, representing the largest gain of any 
patient in the entire trial (n=48).  Further, peak inspiratory and expiratory flow rates (crucial for high velocity 
airflow) improved by 125% and 137%, respectively. Of clinical significance is the fact that the baseline  peak 
expiratory cough flow of this patient (3.8L/s or 228L/min), did not met the physiological requirements to expel 
tracheal aspirate or secretions (threshold: 270L/min). However, peak expiratory cough measures take at the end 
of the clinical trial did (9.0L/s or 540L/min), representing a high-velocity cough proficient for defending the airway. 
In addition, this patient’s forced vital capacity increased from 86% to 97% of predicted, ALSFRS-R Bulbar 
subscale score from a 10 to an 11, functional oral intake score from a 6 to 7 (higher scores = less dietary 
restriction), and swallowing-related quality of life score from an 81 to 90 (higher scores= better reported  
quality of life).  
  
EXPERIMENTAL DESIGN AND METHODS. 
Design.  
This study represents a prospective multicenter trial in 36 individuals with ALS. All eligible and enrolled 
study participants will be administered the study drug, Nuedexta, as recommended by their treating 
neurologists, Drs. James Wymer and Eduardo Locatelli. Once enrolled, participants will be assigned a study 
number and complete a baseline evaluation prior to commencing treatment with Nuedexta.  During the 
baseline assessment, participants will undergo a comprehensive bulbar evaluation of swallowing, airway 
protection and speech functions, and complete validated patient-reported surveys. Following 30-days of 


Page 5 of 14 
Protocol Version 2.0 
 
 
8/1/2019 
Nuedexta treatment, participants will be re-evaluated using the same battery of assessments to determine the 
impact of treatment (Figure 2).   
Participants.  
This open-label study will include 36 individuals with ALS. We will include 
patients demonstrating mild to moderate bulbar involvement to avoid both floor 
and ceiling effects on the outcomes administered. 
 
Inclusion Criterion:  
1) Diagnosis of probable-definite ALS (El-Escorial Criterion); 2)  ALSFRS-R 
Bulbar subscale score <10; 3)  Bamboo oral reading speaking rate <140 words 
per minute; 4)  No allergies to barium sulfate.  
 
Exclusion Criterion:  
1) Treatment for sialorrhea within the past 3 months that includes either Botox 
or radiation treatment; 2) Participation in another disease modifying study 
targeting 
bulbar 
or 
cough 
function; 
3) 
Use 
of 
invasive 
mechanical 
ventilation/presence of tracheostomy; 4) Advanced frontotemporal dementia 
or significant cognitive dysfunction; 5) Nil per oral status for feeding (i.e., NPO, 
nothing by mouth); and 6) Previously prescribed Nuedexta.  Additionally, if 
participants are taking Riluzole or other medications to control sialorrhea, they must be on a stable dose for at 
least 30 days prior to enrollment in the current study.   
 
Subject Withdrawal Criteria 
Inclusion in the study is entirely voluntary and subjects may withdraw at any time for any reason. Subjects wishing 
to stop medication will immediately discontinue test article and the testing procedures. Withdrawal due to adverse 
event will be followed until clearance of sequelae of the adverse event. 
 
Recruitment. 
A total of 36 individuals with ALS between the ages of 18-90 will be recruited for the study. ALS patients will be 
identified and recruited from two large multidisciplinary ALS Centers: 1) the University of Florida Movement 
Disorders Center in Gainesville, Florida (Site #1), and 2) the Phil Smith Neuroscience Institute at Holy Cross 
Hospital in Fort Lauderdale, Florida (Site #2). The PI’s work alongside the treating neurologists at each site to 
identify eligible participants throughout the study (Plowman and Wymer at site 1; Tabor and Locatelli at Site 2).  
Targeted recruitment is 36 participants across sites, with 20 being recruited from the Neuroscience Institute and 
16 from the University of Florida clinic. Census data across both sites indicates feasibility, with an average of 45 
patients seen each month across the study sites.  
 
Informed Consent 
Written informed consent will be obtained from each study participant before any study procedures. The 
participant’s willingness to participate in the study will be documented in writing in a consent form approved by 
an Institutional Review Board. This document will be signed and a copy provided to the participant.  
 
Overview of Experimental Procedures and Outcome Metrics.  
Participants will complete two evaluations (baseline and post-Nuedexta treatment) at each site.  All testing 
procedures and the corresponding outcome measures for Aims 1 – 3 are summarized in Table 1. Measures will 
be administered at two time points to determine if changes in speech and swallowing physiology (Aims 1 and 2) 
or patient perceptions of speech and swallowing function (Aim 3) occur following 30-days of Nuedexta treatment. 
Thirty-days represents a valid time period previously utilized in the original clinical trial investigating the efficacy 
of Nuedexta in improving pseudobulbar affect (Pioro, 2014) and again utilized in the recent PRO clinical trial 
(Smith et al., 2017). This timeframe also represents a pragmatic and feasible timeline to minimize attrition and 
missing data points while ensuring adequate time for potential change in bulbar function.   
 
 
 
 
 


Page 6 of 14 
Protocol Version 2.0 
 
 
8/1/2019 
 
 
Table 1. Summary of testing procedures and corresponding outcome measures for each aim. 
Bulbar 
Domain: 
 
Testing Procedure: 
 
Validated Outcome Measure: 
 
Swallowing 
(Aim 1) 
 
Videofluoroscopic 
Swallowing Evaluation 
Global: Dynamic Imaging Grade Swallowing Toxicity, DIGEST (Hutcheson, 
2017) 
Airway Safety: Penetration Aspiration Scale, PAS (Rosenbek, 1996) 
Swallow Efficiency: Normalized Residue Ratio Scale, NRRS (Pearson et al., 
2013) 
Cough 
(Aim 1) 
Peak Cough Flow Meter 
Peak Cough Flow (L/min)  
Cough Spirometry 
Inspiratory & Expiratory Flow Rates & Durations, Cough Volume 
Acceleration 
 
Speech 
(Aim 2) 
Sustained /a/ 
Maximum Phonation Duration (sec) and Amplitude (dB). 
Diadochokinetics (DDK) 
Number of CV repetitions for /ba/ and for /ta/ 
Sentence Intelligibility 
Test 
Intelligibility (%), Rate (WPM), Communication Efficiency Ratio 
Bamboo Passage 
Intelligibility (%), Rate (WPM), Pause Duration (sec) 
Iowa Oral Perf’ Instrument 
Maximum anterior isometric pressure and Lingual physiologic reserve 
(KPa) 
 
Patient 
Perception  
(Aim 3) 
 
 
Patient Report Outcomes 
Bulbar: Center Neurological Study Bulbar Function Scale, CNS-BFS (Smith, 
2011) 
Swallowing: Eating Assessment Tool-10, EAT-10 (Belafsky, 2008) 
Speech: Communication Participation Item Bank-10, CPIB-10 (Baylor et al., 
2013) 
Global: ALS Functional Rating Scale-Revised, ALSFRS-R (Cedarbaum, 
1999)  
 
Experimental Procedures: 
 
1. Videofluoroscopic Evaluation of Swallowing: Videofluoroscopy will be utilized to visualize bolus flow 
events and swallowing kinematics during the swallow.  Videofluoroscopy will be performed using a Phillips 
BV Endura fluoroscopic C-arm unit (GE OEC 8800 Digital Mobile C-Arm system type 718074) housed within 
the Swallowing Systems Core laboratory (Site #1) and a Shimadzu videofluoroscopy (Flexavision R3 R/F) 
remote room housed within the Neuroscience Institute (Site #2). Videofluoroscopic data will be captured at 
30 frames per second in the lateral field of view using a TIMS Dicom recording system at both sites (Version 
3.2, TIMS Medical, TM, Chelmsford, MA).  ALS individuals will complete a videofluoroscopic evaluation of 
swallowing using the following barium bolus presentations: 5cc thin x2, 20 cc thin x2, 5cc pudding x2, barium 
tablet with thin barium.  All barium bolus presentations will be 
administered by the speech pathologist and all swallows will be cued to 
synchronize with videofluoroscopy.  Participants will be seated in the 
lateral position with the nasal spine, oral cavity, pharynx, cervical spine, 
and upper esophageal sphincter in the viewing plane.  A lapel 
microphone will be utilized to record throat clearing and cough during the 
videofluoroscopy.  To ensure participant safety, a modified bolus 
viscosity, volume or swallowing compensation will be implemented 
following a bail out criterion of ≥3 episodes of frank aspiration with 
ineffective clearance of aspirate material.  Airway safety during 
swallowing, bolus efficiency profiles and global swallowing function will 
be compared within individuals between baseline and final evaluations 
using validated outcome measures.  Both PIs have performed hundreds 
of these exams and an example of a lateral still shot image from Dr. Plowman’s laboratory is shown in Figure 
3 with a C2-4 scalar shown. 
 
2. Cough Spirometry Testing:  
Voluntary cough motor output will be assessed using an oral pneumotachograph (MLT 1000, ADInstruments, 
Inc; Colorado Springs, CO), connected to a disposable spirometry filter (MQ 304 Spirometer Filter, Vacumed; 
Ventura, CA). Prior to assessment, a three-liter syringe will be used to calibrate airflow and volume.  Voluntary 


Page 7 of 14 
Protocol Version 2.0 
 
 
8/1/2019 
cough testing will be completed in a seated position, with nose clips in place to 
occlude nasal airflow.  Participants will be instructed to hold the spirometry filter 
comfortably and place their mouth around the mouthpiece prior to starting the task.  
The clinician will provide assistance for participants who are not able to hold the 
device due to limb immobility. The clinician will provide a model prior to the task 
using the following instructions: “Cough hard, like you have something stuck in 
your throat.” This procedure will be repeated three times, with the identical 
instruction given prior to each trial.  The airflow signal will be recorded online to an 
iMac desktop computer (Apple, Inc. USA) using Lab Chart (AD Instruments, Inc. 
Version 8), and low pass filtered at 60 Hz for subsequent analysis.  The first cough 
of each epoch (i.e., series of coughs) will be analyzed, yielding a total of three 
coughs per participant.  The maximum cough airflow parameters of the three 
coughs will be utilized for analysis for each participant. Examples of previously 
collected voluntary cough spirometry airflow from individuals with ALS are 
provided in both Figures 1 and 9. 
 
3. Peak Cough Flow Testing: 
Peak cough flow will be assessed using a commercially available handheld digital peak cough flow meter  
(MicroLife PF100). With the participant comfortably seated, and wearing nose clips, they will be instructed to 
take a deep breath in and then to “cough hard like you have something stuck in your throat” (into the peak flow 
meter). An example of peak cough flow testing is provided in Figure 4. Three trials will be performed with the 
best result used for subsequent statistical analyses. 
 
4. Speech Testing: 
Speech testing will occur with the 
participant comfortably seated at a 
standardized 
distance 
from 
a 
computer 
screen. 
A 
digital 
audio 
recorder (TASCAM, DR40) connected 
to a condenser headset microphone 
(AKG, Inc., HSC271) with a lapel 
windscreen (eBoot, Inc.) will be placed 
on the participants head with the 
headset microphone at a standardized 
distance of 10cm from the right lip 
corner. 
Audio 
recordings 
will 
be 
digitized at 44.1 kHz with a 16-bit 
quantization. 
Calibration 
of 
the 
microphone will be completed prior to 
each test. Speech testing items will be 
recorded and saved for subsequent 
offline analysis. An example of our 
experimental 
speech 
testing 
setup 
and 
collected 
speech 
data 
are 
provided in Figure 5.  
Each participant will complete four speech tasks at the baseline and final evaluation time points that include: 
a. Sustained /a/: The participant will be instructed to take a deep breath in and then sustain the vowel 
‘ah’ (as in father) for as long and steady as possible at a comfortable pitch and loudness. 
b. Diadochokinetics (DDK): The participant will be asked to perform two DDK tasks for the CV 
combinations of /ba/ and /ta/. They will be asked to take a deep breath in, and then on one breath 
repeat the CV combination “ba” as many times as they can until they run out of breath. They will be 
instructed “Take a deep breath. Say “ba” as clearly and as fast as you can, for as long as you can. 
/Ba-ba-ba-ba-ba-ba-ba…./”. The same instructions will be provided for the /ta/ DDK task. 
c. 
Speech Intelligibility Test (SIT): The abbreviated 10-item SIT assessment (SIT for Windows, 
Madonna Rehabilitation) will be performed. This is a widely used assessment to determine speaking 
intelligibility of persons with motor speech impairments during oral reading tasks. Participants will be 


Page 8 of 14 
Protocol Version 2.0 
 
 
8/1/2019 
given ten randomly generated sentences, which get progressively longer in word and sentence 
length, to read aloud at a comfortable speaking rate and loudness. Sentence intelligibility, speaking 
rate and communicative efficiency will be generated for analysis.  
d. Bamboo Passage Reading: The ‘Bamboo Passage’ is a validated speech testing item developed 
specifically for individuals with ALS to determine speaking rate, and number and duration of pauses 
during speech (Green et al., 2004). The clinician will instruct the participant to read the passage in 
their normal speaking rate and loudness.  
 
5. Lingual Strength Testing: 
Lingual strength testing will be performed using the Iowa Oral Performance Instrument (IOPI,  IOPI Medical 
LLC, Woodinville,WA). This is a commercially available device used to 
index tongue strength using a handheld, portable unit that connects to an 
air-filled pressure bulb using a connector cable. With the participant 
comfortably seated, they will be introduced to the device and bulb, and 
instructed to place the lingual bulb directly behind the central incisors to 
rest on the alveolar ridge (Figure 6). The participant will be provided a 
diagram of bulb placement in the oral cavity to facilitate correct placement 
and the examiner will verify placement of the bulb. Once in place, the 
participant will complete two tasks, each three times, and the highest 
recording will be used for subsequent analysis. The participant will be 
instructed to raise the front portion of their tongue and press as hard as 
they can onto the bulb. The bulb will remain in the same placement and 
the participant will be instructed to swallow their saliva normally with the 
bulb in place. Water will be provided between tasks as needed to facilitate 
swallow initiation.  
 
6. Patient Reported Outcomes: 
Four patient report outcomes will be administered to the participant at baseline and final evaluations. Using 
REDCap, an electronic database capturing system, participants will be electronically sent surveys prior to 
their appointment to complete in the comfort of their own home to minimize appointment times. Should they 
require special assistance, we will ask a caregiver to help with reading or entering the data (they will be 
instructed not to influence the participant or help with scoring). The participant will also be afforded the option 
to fill out surveys during their clinic appointment if they prefer. The following items will be administered: 
 
a) Center Neurological Study Bulbar Function Scale, CNS-BFS (Smith, 2011): The CNS-BFS is a 21-item 
validated, patient-reported scale indexing degree of bulbar dysfunction in the domains of speech, 
salivation and swallowing. A copy of the CNS-BFS appears in Appendix A. 
b) Eating Assessment Tool-10 (Belafsky, 2008):The EAT-10 is a 10-item validated self report scale 
indexing an individuals perceived level of swallowing impairment. Patients rate each of the 10 items on 
a 5 point ordinal scale (0=no impairment, 4=severe impairment) with a total EAT-10 score ranging 
between 1 and 40. A copy of the EAT-10 appears in Appendix B. 
c) 
Communication Participation Item Bank-10, CPIB-10 (Baylor et al., 2013): The CPIB-10 is a 10-item 
validated, patient-reported survey assessing communicative effectiveness across contexts ranging 
from 0 (ineffective) to 30 (effective). A copy of the CPIB-10 appears in Appendix C.  
d) ALS Functional Rating Scale-Revised, ALSFRS-R (Cedarbaum, 1999): The ALSFRS-R is the 
validated, gold standard survey assessing ALS symptom and disease progression to determine disease 
severity ranging from 0 (severe disease symptomology) to 48 (no overt symptoms). A copy of the 
ALSFRS-R appears in Appendix D. 
 
Outcome Measures: 
All swallow, cough or speech physiologic outcomes will be double-rated by two experienced and independent 
raters. They will be blinded to participant ID and also to the test number. If any discrepancies in ratings occur, a 
consensus meeting will held and if needed, a third rater will be consulted until agreement can be reached. 
 
Global Swallowing Function: The validated Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) will be 
performed on all collected videofluoroscopic swallowing studies to assess global swallowing function (Hutcheson 


Page 9 of 14 
Protocol Version 2.0 
 
 
8/1/2019 
and Fuller, 2015). The DIGEST total score is determined using the composite of individual airway safety and 
bolus efficiency subscores (range: 0-4). The DIGEST total is rated on a 5-point ordinal score ranging from 0 (no 
dysphagia) to 4 (life-threatening dysphagia).  For statistical analysis, DIGEST total scores will be compared 
within individuals between the baseline and final evaluation time points. DIGEST total scores of <2 indicate 
functional swallowing and scores ≥ 2 indicate dysphagia. The DIGEST scoring schema is provided in Appendix 
E. 
 
Swallowing Safety:  
The Penetration-Aspiration scale (PAS, (Rosenbek et al., 1996) 
is a validated eight-point ordinal scale indexing the degree of 
airway invasion during swallowing, the participant’s response, 
and whether the invasive material is successfully ejected from 
the airway (Figure 7). PAS scores of 1 and 2 are considered 
safe, while scores between 3 and 5 indicate penetration of 
material in the upper airway at or above the level of the true 
vocal folds. PAS scores greater than 6 indicate aspiration of 
material below the level of the true vocal folds into the airway. 
For statistical comparisons across airway safety status levels 
the convention is as follow: safe swallowing = PAS <2 and 
unsafe swallowing= PAS>3. Figure 7 depicts the PAS and 
denotes airway safety groups with representative lateral 
fluoroscopy images representative of each swallowing safety 
group collected from our labs. 
 
Swallowing Efficiency:  
The validated Normalized Residue Ratio Scale (NRRS, (Pearson et al., 2013) provides a quantitative ratio-based 
measure of post-swallow pharyngeal residue in the valleculae and piriform sinus (Figure 8). A single frame from 
the each videofluoroscopy clip will be selected by rater consensus, and ImageJ (ImageJ, free software) will be 
utilized to derive pixel-based measurements within the pharynx. Specific measurements include: vallecular 
housing area, vallecular residue, piriform sinus area, piriform sinus residue piriform sinus residue and a C2-C4 
anatomical scalar. These will be utilized to calculate severity of pharyngeal residue and are calculated using the 
area ratio for the valleculae multiplied by 
the 
area 
of 
the 
valleculae 
residue 
divided by an internal scalar (C2-C4) to 
account 
for 
individual 
anatomical 
differences. The same calculation using 
the piriform area and residue is utilized 
to determine NRRS of the piriforms. All 
NRRS ratings will be double rated and 
inter and intra-rater reliability completed 
prior to further statistical analysis. NRRS 
vallecular and piriform sinus values will 
be compared within-subjects between 
baseline 
and 
final 
evaluations. 
In 
addition, NRRSv values greater than 
0.07 and NRRSp values greater than 
0.20 
indicate 
greater 
than 
normal 
residue and thus inefficient swallowing.   
 
Cough Function:  
Peak cough flow (L/min) and forced expiratory volume within the first second (FEV1) will be derived from peak 
cough flow testing. The highest flow obtained from three trials will be utilized. Cough spirometry airflow output 
will be analyzed and six cough parameters derived. The highest values obtained during a single cough epoch 
will be utilized for analysis.  Each parameter is defined and illustrated in Figure 9 below. 


Page 10 of 14 
Protocol Version 2.0 
 
 
8/1/2019 
Lingual Strength Outcomes:  
The following outcomes will be derived from the IOPI testing. The highest maximum anterior isometric pressure 
and saliva swallowing pressure will be utilized and these metrics will be derived at time of testing. Lingual 
physiological reserve will be calculated from obtained data. 
a) Maximum Anterior Isometric Pressure (MAIP) (KPa). 
b) Saliva Swallowing Pressure (KPa) 
c) 
Lingual Physiologic Reserve (LPR) = Maximum anterior isometric pressure – saliva swallow pressure 
 
Speech Outcomes: 
Audio recordings obtained during speech testing will be blinded and rated in Audacity (Audacity 2.2.2, 
WordPress, 2018) for the below speech outcomes.   
 
Table 2. Speech outcomes delineated by speech task. 
 
Speech Task 
Derived Outcomes: 
Sustained /ah/ 
Vowel duration (/ah/,sec), maximum amplitude (dB), amplitude fluctuation, pitch 
fluctuation 
DDK 
Maximum number of consonant-vowel repetitions produced for /ba/ task and /ta/ task 
Speech 
Intelligibility 
Test 
Intelligibility (%): (number of spoken words correctly transcribed / 110 words spoken) 
Rate: words per minute = (number of words / 60 * duration of oral reading in seconds) 
Communication efficiency ratio= (rate of intelligible speech / rate of speech of healthy 
adults) 
Bamboo 
Passage  
Intelligibility (%): (number of spoken words correctly transcribed / 98 words spoken) 
Rate: Words per minute= (number of words / 60 * duration of oral reading in seconds) 
Number of Pauses 
Duration of Pauses 
 
Patient-Reported Outcomes:  
a) CNS-BFS: The following scores will be calculated. Total CNS-BFS score (range: 21-111); CNS-BFS 
Speech subscale score (range: 7-41); CNS-BFS Salivation subscale score (range: 7-35) and CNS-BFS 
Swallowing subscale score (range: 7-35). 
b) EAT-10: A total EAT-10 score will be derived and will range between 0 (no impairment) and 40 (severe 
impairment).  
c) 
CPIB-10: A total CPIB-10 score will be derived and will range between 0 (severe impairment) and 30 
(no impairment).  
d) ALSFRS-R: A total ALSFRS-R score will be calculated (range: 0-48) as well as a Bulbar ALSFRS-R 
Subscale score (range: 0-12). 
 
 


Page 11 of 14 
Protocol Version 2.0 
 
 
8/1/2019 
Statistical Considerations. 
Sample Size: Robust improvements in pseudobulbar affect and patient-reported bulbar function were reported 
following Nuedexta treatment in individuals with ALS, therefore, clinically significant improvements in physiologic 
parameters of speech and swallow functions are hypothesized (Pioro, 2014).  A sample of 30 participants is 
needed to detect clinically relevant changes in bulbar physiology and function. For repeated measure analyses, 
this sample will be able to detect minimum differences (between baseline and final evaluations) of 1 L/min peak 
expiratory flow rate and 25% differences in ordinal outcomes (i.e., PAS, DIGEST). Given that this study 
represents the first to investigate the impact of Nuedexta on speech function, we utilized a minimal detectable 
difference for N=30 of 10 words per minute during the oral reading task for the sample size determination. We 
will recruit an additional 6 participants, assuming a 20% dropout rate to ensure we meet our target data collection 
number. 
 
Data Analyses. 
Dr. Terrie Vasilopoulos, a consultant on this project, will perform all statistical analyses.  Analyses will be 
completed using IBM SPSS Software (Version 24) and SAS Software (SAS Inst., Cary, NC).  P<0.05 will be 
considered statistically significant. Intra- and Inter- rater reliability will be performed on all non-automated ratings 
using the intraclass correlation coefficient.  To assess the impact of Nuedexta on swallow, cough, lingual, speech 
and PRO metrics a repeated measure analysis of variance (ANOVA) model will be used (parametric variables) 
and a Wilcoxon signed rank test (non-parametric data) with alpha set at 0.05. Corrections for multiple 
comparisons will be implemented, as needed.  
 
Data Management and Safety Monitoring and Adverse Event Reporting. 
Data will be collected across two time points (baseline and post-Nuedexta treatment) at both sites using a 
centralized data management program (REDCap) for surveys and physiologic data that do not require post-
testing analyses. REDCap is an electronic data capture system used for research with a software toolset and 
workflow methodology for electronic collection and management of research and clinical trial data. REDCap is a 
scalable, secure, enterprise-level application. The software is delivered via 256 bit SSL-encryption, and features: 
1) an intuitive interface for the creation of case report forms (CRFs) and validated data entry; 2) audit trails for 
tracking data manipulation and export procedures; 3) procedures for importing data from external sources; the 
ability to relate CRFs to study events and schedule them via a calendar function; and 4) automated export 
procedures for seamless data downloads to common statistical packages (SPSS, SAS, STATA, R). Data from 
both sites will be uploaded and accessible through the secured REDCap database.  
 
The UF-IRB will review the human subject protocol and will monitor the quality of research occurring under the 
approved protocol. The IRB must approve the protocol annually, as the study progresses.  Data safety monitoring 
will occur during weekly meetings to review Adverse Events and Protocol Deviation Logs with the PI and study 
team. In the event of an unanticipated adverse response, the participant’s physician will be immediately notified 
and the patient will be seen for a complete evaluation. Data, adverse events, and individual subject safety are 
monitored throughout each subject’s evaluation as well as during weekly laboratory meetings with the PI and 
study team that adhere to the UF IRB regulations for reporting of AE’s and protocol deviations. Addtionally, 
monthly conference calls between sites will occur to share or discuss any adverse events or protocol deviations.  
Study Drug Handling and Dispensing.  
To offset costs in this small scale grant, the study drug will be clinically recommended and obtained through 
each participant’s standard insurance. Per Drs. Wymer and Locatelli recommendation, Nuedexta will be 
prescribed in clinic as medically necessary and participants will be subsequently enrolled in the study. All 
participants will complete their baseline evaluation prior to starting the study drug.  
 
Study Drug Administration and Dosing 
The drug will be administered per the efficacy and safety protocol, with no changes in administration method or 
recommended dose for individuals with ALS. Specifically, Nuedexta (20 mg dextromethorphan HBr and 10mg 
quinidine sulfate) will be administered orally with 1 capsule every day for the initial 7 days followed by 1 capsule 
every 12 hours for the remaining 23 days of the study. Medication will be taken whole and should not be divided, 
crushed, chewed or dissolved.  
 
Study Timeline.  


Page 12 of 14 
Protocol Version 2.0 
 
 
8/1/2019 
Participants will be enrolled March 2019- March 2020, with all participants’ final evaluations completed by 
October 2020 to permit time for final data analysis and manuscript preparation. An overview of the proposed 
experimental timeline is detailed in Figure 10. 
 
 
Study Timeline 
March 2019 
March 2019-March 2020 
March-December 
2020 
December-March 2021 
Obtain IRB 
approval 
(Sites 1 and 2) 
Study commencement 
Enroll and complete 20 
participants 
Enroll and complete 
10 participants 
Final data analysis and 
manuscript preparation 
Ongoing Recruitment and Data Management 
 
 
Potential Pitfalls and Limitations. 
Drug Tolerability and Attrition. 
Nuedexta is approved by the United States Food and Drug Administration and has been proven safe and 
tolerable in several neurological populations including ALS (Pioro, 2014). In the event a participant cannot 
tolerate the medication, or chooses to discontinue use, they will be considered a drop out of the study. Subject 
compliance will be assessed at both visits with questioning about compliance and adverse events. 
 
Competing Trials. 
Participation in the current study requires the subject to be on a steady dose of additional medications that impact 
overall disease progression (i.e., Riluzole). Participation in other disease modifying studies targeting bulbar or 
cough function represents an exclusion criteria for this study. Given that this protocol is only 30 days, we 
anticipate that interested ALS individuals will be immediately enrolled in the current study and then, once 
completed, be offered participation in other potentially disease modifying treatments. The PI’s will communicate 
and closely monitor potential participation in novel experimental treatments that may impact bulbar function 
during the course of the study.  Additionally, information regarding standard of care ALS treatments and 
interventions (i.e., cough assist, BiPap, medications) will be monitored and recorded throughout study 
participation. 
 
Patient Recruitment. 
ALS is considered a rare disease, with a prevalence of 4 in every 100,000 people (Mehta et al., 2014)  and 
patient recruitment and attrition often inhibits successful completion of trials in ALS. To mitigate potential 
limitations in recruitment, we are working with and recruiting from two large ALS Centers in Florida including: 
University of Florida- Gainesville (Dr. Plowman) and the Neuroscience Institute (Dr. Tabor).  Nuedexta is 
commonly prescribed in their respective multidisciplinary ALS clinics and both Centers are actively involved in 
research. Further, both PI’s work closely with the clinic neurologists (Drs. Wymer and Locatelli) and census data 
indicates feasibility for the proposed study sample size. Additionally, Florida has the second highest prevalence 
of ALS patients in the United States. Therefore, we do not anticipate patient recruitment being a limitation. 
 
Multisite Design. 
Standardization of procedures and selected outcomes can represent a potential pitfall in multi-center clinical 
trials. The PI at study site 2 (Dr. Tabor) was trained for 8 years by Dr. Plowman and has previously run large 
clinical trials for Dr. Plowman during her training in the Swallowing Systems Core. The two PI’s are therefore 
extremely calibrated in terms of methods, approaches and analytical techniques. Further, they have identical set 
ups of equipment making such a multisite seamless. Another potential limitation of multi-site trials is 
communication across sites. Given the long history of the two PI’s and a well established track record including 
approximately 15 publications and successful completion of previous collaborative studies, we view this as a 
potential strength. Nonetheless, we set in place a monthly conference calls and a quarterly site visit to mitigate 
potential issues with communications across study sites. Further, the use of REDCap will facilitate collaboration, 
data management and ease of data sharing throughout the duration of the study. 
Figure 10. Proposed study timeline.  


Page 13 of 14 
Protocol Version 2.0 
 
 
8/1/2019 
 
The University of Florida is the lead site and will be responsible for ensuring that both sites have the most current 
version of the protocol and consent/HIPAA documents. All required approvals (initial, continuing review, and 
modifications) will be obtained at each site independently (including by the site’s IRB of record). All modifications 
will be communicated to sites, and approved (including approval by the site’s IRB of record) before the 
modification is implemented. All engaged participating sites will safeguard data, including secure transmission 
of data, as required by local information security policies.  All local site investigators will conduct the study in 
accordance with applicable federal regulations and local laws. All non-compliance with the study protocol or 
applicable requirements will be reported in accordance with University or local policy. 
 
Routine practices for ensuring the confidentiality and privacy of all participants will be followed in this study. All 
research personnel at the University of Florida are required to sign a confidentiality agreement at the time of hire. 
Research personnel at the Phil Smith Neuroscience Institute at Holy Cross Hospital are similarly bound by a 
confidentiality agreement outlined by the ethics board at their institution. Participants will be assigned a non-
identifying alphanumeric study code, and the master key for this code will be retained separately by the PI and 
study coordinator in a password-protected file on a secure, password-protected, encrypted research server. Daily 
back-up of this research server is performed to protect against data loss.  
 
Additionally, any data transfer will occur utilizing REDCap. The transfer of anonymized data containing the 
information needed for analysis will be covered by a data transfer and sharing agreement. A data transfer 
agreement is currently being written up between the two sites and will be completely finalized prior to study 
commencement. 
 
Possible Risks and Discomforts  
Although the videofluoroscopic swallowing study represents the gold standard clinical swallowing exam and 
utilizes an amount of radiation that is thought to be minor, repeated exposures may increase a participant’s risk 
of injury or disease. We will utilize a five minute time cap on actual exposure time to minimize raditation exposure 
to participants. Additionally, the swallowing study also incorporates the use of barium into the protocol. Some 
participants might ingest small amounts of barium into their lungs during the swallowing study causing them to 
cough or feel discomfort.  
 
Possible Benefits 
There is no guarantee that participants will benefit from participating in this study; their condition may improve, 
worsen, or remain the same. Nuedexta has the potential to provide complementary benefits to improve 
swallowing and speech in people with ALS. Improvement in these parameters will effectively prolong survival 
and quality of life for people living with ALS. 
 
Conflict of Interest 
None of the study members have a conflict interest in regard to this study.  
 
Overall Significance and Future Research. 
The proposed study addresses a critical management gap in individuals with ALS. Currently, there exist no 
efficacious treatments to maintain and prolong bulbar function and no group has examined the physiologic impact 
of this promising pharmacological intervention, Nuedexta, on speech and swallowing function and physiology in 
this challenging patient population.  This proposal will provide the first dataset to determine the potential 
therapeutic role of Nuedexta for the management of bulbar dysfunction in ALS.  Better treatments will lead to 
improvements in quality of life, functional oral intake, nutrition, communicative effectiveness, pulmonary health 
and ultimately survival in this patient population. Results of this work will provide valuable insight into a potentially 
beneficial therapeutic, disease modifying treatment for bulbar dysfunction, highlighting a departure from status 
quo treatment options. 
 
 
 


Page 14 of 14 
Protocol Version 2.0 
 
 
8/1/2019 
References: 
 
Baylor C, Yorkston K, Eadie T, Kim J, Chung H, Amtmann D (2013) The Communicative Participation Item Bank 
(CPIB): item bank calibration and development of a disorder-generic short form. Journal of speech, 
language, and hearing research : JSLHR 56:1190-1208. 
Boitano LJ (2006) Management of airway clearance in neuromuscular disease. Respiratory care 51:913-922; 
discussion 922-914. 
Bouteloup C, Desport JC, Clavelou P, Guy N, Derumeaux-Burel H, Ferrier A, Couratier P (2009) 
Hypermetabolism in ALS patients: an early and persistent phenomenon. Journal of neurology 256:1236-
1242. 
Carpenter R, McDonald T, Howard Jr F (1977) The otolaryngologic presentation of amyotrophic lateral sclerosis. 
Otolaryngology 86:ORL479-484. 
Green JR, Beukelman DR, Ball LJ (2004) Algorithmic Estimation of Pauses in Extended Speech Samples of 
Dysarthric and Typical Speech. Journal of medical speech-language pathology 12:149-154. 
Hillel AD, Miller R (1989) Bulbar amyotrophic lateral sclerosis: patterns of progression and clinical management. 
Head & neck 11:51-59. 
Hutcheson K, Barringer, D., Knott, JK., Lin, H. , Weber, RS.,, Fuller C, Lazarus, C., May, AH., Patterson, JM., 
Roe, J., Starmer, HM., Lewin, JS. (2015) DYNAMIC IMAGING GRADE OF SWALLOWING TOXICITY 
(DIGEST): SCALE DEVELOPMENT AND VALIDATION. In: Dysphagia Research Society. 
Kühnlein P, Gdynia H-J, Sperfeld A-D, Lindner-Pfleghar B, Ludolph AC, Prosiegel M, Riecker A (2008) Diagnosis 
and treatment of bulbar symptoms in amyotrophic lateral sclerosis. Nature Clinical Practice Neurology 
4:366-375. 
Mehta P, Antao V, Kaye W, Sanchez M, Williamson D, Bryan L, Muravov O, Horton K (2014) Prevalence of 
Amyotrophic Lateral Sclerosis — United States, 2010-2011. MMWR Surveillance Summaries 63:1-13. 
Miller RG, Jackson CE, Kasarskis EJ, England JD, Forshew D, Johnston W, Kalra S, Katz JS, Mitsumoto H, 
Rosenfeld J, Shoesmith C, Strong MJ, Woolley SC (2009) Practice Parameter update: The care of the 
patient 
with 
amyotrophic 
lateral 
sclerosis: 
Multidisciplinary 
care, 
symptom 
management, 
and 
cognitive/behavioral impairment (an evidence-based review): Report of the Quality Standards 
Subcommittee of the American Academy of Neurology. Neurology 73:1227-1233. 
Paganoni S, Karam C, Joyce N, Bedlack R, Carter GT (2015) Comprehensive Rehabilitative Care Across the 
Spectrum of Amyotrophic Lateral Sclerosis. NeuroRehabilitation 37:53-68. 
Pearson WG, Jr., Molfenter SM, Smith ZM, Steele CM (2013) Image-based measurement of post-swallow 
residue: the normalized residue ratio scale. Dysphagia 28:167-177. 
Pioro EP (2014) Review of Dextromethorphan 20 mg/Quinidine 10 mg (NUEDEXTA((R))) for Pseudobulbar 
Affect. Neurology and therapy 3:15-28. 
Plowman EK, Tabor LC, Wymer J, Pattee G (2017) The evaluation of bulbar dysfunction in amyotrophic lateral 
sclerosis: survey of clinical practice patterns in the United States. Amyotrophic Lateral Sclerosis and 
Frontotemporal Degeneration:1-7. 
Plowman EK, Tabor-Gray L, Rosado KM, Vasilopoulos T, Robison R, Chapin JL, Gaziano J, Vu T, Gooch C 
(2018) Impact of expiratory strength training in amyotrophic lateral sclerosis: Results of a randomized 
sham controlled trial. Muscle & nerve. 
Rosenbek JC, Robbins JA, Roecker EB, Coyle JL, Wood JL (1996) A penetration-aspiration scale. Dysphagia 
11:93-98. 
Smith R, Pioro E, Myers K, Sirdofsky M, Goslin K, Meekins G, Yu H, Wymer J, Cudkowicz M, Macklin EA, 
Schoenfeld D, Pattee G (2017) Enhanced Bulbar Function in Amyotrophic Lateral Sclerosis: The 
Nuedexta Treatment Trial. Neurotherapeutics : the journal of the American Society for Experimental 
NeuroTherapeutics 14:762-772. 
Tabor L, Gaziano J, Watts S, Robison R, Plowman EK (2016) Defining Swallowing-Related Quality of Life 
Profiles in Individuals with Amyotrophic Lateral Sclerosis. Dysphagia. 
 
 

ICF_001.pdf: 
 
Impact of Nuedexta on Bulbar Physiology and Function in ALS 
 
NCT03883581 
 
 
Informed Consent Form 


IRB APPROVED 
AS MODIFIED 
Aug 21, 2019 
 
L. Tabor-Gray 
Protocol Version #2 
Page 2 of 10 
Version Date: 08/06/2019 
ALS Association Clinical Management Grant 
WIRB® Protocol #20190853 
 
RESEARCH SUBJECT INFORMATION AND CONSENT FORM 
TITLE:   
Impact of Nuedexta on Bulbar Physiology and Function in ALS 
 
This consent form contains important information to help you decide whether to participate 
in a research study. 
 
The study staff will explain this study to you.  Ask questions about anything that is not clear at any 
time.  You may take home an unsigned copy of this consent form to think about and discuss with 
family or friends.   
 
• Being in a study is voluntary – your choice. 
• If you join this study, you can still stop at any time. 
• No one can promise that a study will help you. 
• Do not join this study unless all of your questions are answered. 
 
After reading and discussing the information in this consent 
form you should know: 
 
1. Why this research study is being done; 
2. What will happen during the study; 
3. Any possible benefits to you; 
4. The possible risks to you; 
5. Other options you could choose instead of being in this study;  
6. How your personal health information will be treated during the study 
and after the study is over; 
7. Whether being in this study could involve any cost to you; and 
8. What to do if you have problems or questions about this study. 
 
Please read this consent form carefully. 


IRB APPROVED 
AS MODIFIED 
Aug 21, 2019 
 
L. Tabor-Gray 
Protocol Version #2 
Page 3 of 10 
Version Date: 08/06/2019 
RESEARCH SUBJECT CONSENT FORM 
 
Title: 
Impact of Nuedexta on Bulbar Physiology and Function in 
ALS 
 
Protocol No.:  
None 
 
WIRB® Protocol #20190853 
 
Sponsor:  
ALS Association Clinical Management Grant  
 
Investigator: 
Lauren Tabor-Gray, PhD 
 
4725 N. Federal Highway 
 
Fort Lauderdale, FL 33308 
 
USA 
 
Daytime Phone Number:  
954 542 3429 
 
24-hour Phone Number:  
443 536 1234 
 
Initial Concise Summary 
 
Introduction 
You are invited to participate as a volunteer in this clinical research study, which is funded 
by the ALS Association. Your participation in the study is voluntary. You have the right to 
decide whether or not to participate in this study without penalty.  If you decide to participate 
in this study, you can withdraw at any time without penalty. During the study, you will be 
informed of any new information on the study drug that might affect whether you want to 
continue participating in the study.  The study doctors or a designated study staff member can 
decide to withdraw you from this study, without your consent, if they judge that it would be 
better for your health.   You could also be withdrawn from this study if you do not follow 
the instructions given to you or for other reasons as well.  If you are withdrawn from the 
study by the principal investigator or study staff, the reason for your withdrawal will be 
explained to you. At the time of your withdrawal from the study, you may be asked to 
undergo additional tests for your safety. 
 
In total, there will be approximately thirty (30) volunteers with amyotrophic lateral sclerosis 
(ALS) participating in this study. 
 
This INFORMATION AND CONSENT FORM is intended to give you an overview of this 
clinical research study and what it involves. It may contain words that you do not 
understand. Please ask the principal investigator or a member of the study staff to explain 
any words or information that you do not understand. If you decide to participate in this 
study, you will be asked to sign and date this INFORMATION AND CONSENT FORM. 
This will confirm that you have been informed of the nature of the study and what it 
involves.  Signing of this INFORMATION AND CONSENT FORM does not take away 
any of your legal rights.  You will be given a copy of the INFORMATION AND 
CONSENT FORM after you have signed and dated it.  During the study, if there is any 


IRB APPROVED 
AS MODIFIED 
Aug 21, 2019 
 
L. Tabor-Gray 
Protocol Version #2 
Page 4 of 10 
Version Date: 08/06/2019 
new information on the study drug, you will be notified and provided an amendment to the 
INFORMATION AND CONSENT FORM for your signature. 
 
Information about the Research 
Speech and swallowing difficulties occur throughout disease progression in individuals with 
ALS, who rate these symptoms as the worst aspect of the disease (Hillel and Miller, 1989). 
These impairments lead to social isolation and withdrawal, reduced quality of life and mental 
wellbeing, malnutrition, and aspiration pneumonia. A current gap in the clinical care of 
individuals with ALS is effective treatments to either improve or maintain speech and 
swallowing function. A promising drug is already approved by the FDA for use in ALS 
patients, Nuedexta, was recently documented to improve patient-rated speech and swallowing 
function (Smith et al., 2016). While this is promising, no study has yet determined the impact 
this pharmacologic intervention has on objective clinical and physiologic outcomes of speech 
and swallowing in ALS patients. The primary goal of this proposal is to rigorously evaluate the 
impact of an investigational pharmacological treatment, Nuedexta, on swallowing physiology, 
airway protection and speech intelligibility in individuals with ALS. Outcomes of this work 
will provide valuable physiologic insight into a promising therapeutic and help to reduce 
current gaps in the clinical management of individuals with ALS. 
 
RESEARCH CONSENT SUMMARY 
You are being asked for your consent to take part in a research study. This document provides a 
concise summary of this research. It describes the key information that we believe most people 
need to decide whether to take part in this research. Later sections of this document will 
provide all relevant details. 
 
What should I know about this research? 
• Someone will explain this research to you. 
• Taking part in this research is voluntary. Whether you take part is up to you. 
• If you don't take part, it won't be held against you. 
• You can take part now and later drop out, and it won't be held against you 
• If you don't understand, ask questions. 
• Ask all the questions you want before you decide. 
 
How long will I be in this research? 
We expect that your taking part in this research will last 30 days. 
 
Why is this research being done? 
Speech and swallowing difficulties occur throughout disease progression in individuals with 
Amyotrophic Lateral Sclerosis (ALS) who rate these symptoms as the worst aspects of the 
disease (Hillel and Miller, 1989). There are currently no effective treatments for speech and 
swallowing impairment in ALS.  The purpose of this research is to determine if Nuedexta, an 
FDA approved and routinely prescribed medication, improves speech and swallowing 
functions in patients with ALS. 
 
What happens to me if I agree to take part in this research? 
If you decide to take part in this research study, the general procedures include returning to the 
Phil Smith ALS Clinic for two visits spaced one month apart.  Each visit will take 
approximately 1.5 hours. The first visit will occur prior to you starting Nuedexta and the 
second visit will occur one month after your first Nuedexta dose. During the research study, 


IRB APPROVED 
AS MODIFIED 
Aug 21, 2019 
 
L. Tabor-Gray 
Protocol Version #2 
Page 5 of 10 
Version Date: 08/06/2019 
Nuedexta will be taken according to FDA approved dosage at one time per day for the first 7 
days and then one time every 12 hours (two times per day) for the remaining 23 days of the 
study. 
 
During each visit, you will undergo tests to look at your swallowing, speech and ability to 
cough doing standard clinical exams. You will also be asked to fill out surveys on your ability 
to swallow and communicate. You will complete the following tests: 
 
Swallowing X-Ray Study: During the swallowing portion of examination we will take an X-
ray of your swallowing, this is called a Videofluoroscopy and is like a movie x-ray of you 
swallowing foods and liquids. For this test you will be asked to sit comfortably in chair and 
swallow barium. Barium is a substance that allows us to see how food and liquids flow 
through your mouth, throat, and esophagus during x-ray. It is white to the naked eye, but 
appears black in the x-ray. Barium may be thin, liquid, nectar, honey, or paste consistencies. 
You cannot feel the x-ray while it is on and the total time that the x-ray machine will be on 
will be under three-minutes (although the test will take approximately ten-minutes). 
 
Cough Testing: We will ask you to cough into special equipment to measure the maximum 
strength of your cough. 
 
Tongue Pressure Examination: During the tongue examination, we will measure your 
tongue strength by testing your ability to apply pressure to an air-filled tongue bulb that will 
rest on the roof of your mouth. 
 
Speech Testing: We will record your speech using a small headset microphone as you read 
sentences and a short passage aloud. 
 
Patient-reported Surveys: You will be asked to complete four routinely administered patient 
surveys including: 
1. Center Neurological Study Bulbar Function Scale, CNS-BFS (Smith, 2011): The 
CNS-BFS is a 21-item validated, patient-reported scale indexing degree of bulbar 
dysfunction in the domains of speech, salivation and swallowing. A copy of the 
CNS- BFS appears in Appendix A. 
2. Eating Assessment Tool-10 (Belafsky, 2008):The EAT-10 is a 10-item validated self 
report scale indexing an individuals perceived level of swallowing impairment. Patients 
rate each of the 10 items on a 5 point ordinal scale (O=no impairment,4=severe 
impairment) with a total EAT-10 score ranging between 1 and 40. A copy of the EAT-
10 appears in Appendix B. 
3. Communication Participation Item Bank-10, CPIB-10 (Baylor et al., 2013): The CPIB-
10 is a 10-item validated, patient-reported survey assessing communicative 
effectiveness across contexts ranging from 0 (ineffective) to 30 (effective). A copy of 
the CPIB-10 appears in Appendix C. 
4.  ALS Functional Rating Scale-Revised, ALSFRS-R (Cedarbaum, 1999): The ALSFRS- 
R is the validated, gold standard survey assessing ALS symptom and disease 
progression to determine disease severity ranging from 0 (severe disease 
symptomology) to 48 (no overt symptoms). A copy of the ALSFRS-R appears in 
Appendix D. 
 


IRB APPROVED 
AS MODIFIED 
Aug 21, 2019 
 
L. Tabor-Gray 
Protocol Version #2 
Page 6 of 10 
Version Date: 08/06/2019 
At the conclusion of the research study, we will review the results of the swallowing, cough, 
tongue and speech testing measurements and compare them to your first visit. You can 
continue taking the study drug after the study is completed. 
 
Could being in this research hurt me? 
Nuedexta has been demonstrated to be safe and well-tolerated in patients with ALS. 
However, the most important risks or discomforts that you may expect from taking part in 
this research include side effects of the medication such as diarrhea, dizziness, cough, 
vomiting, asthenia, swelling, urinary tract infection, influenza and gas pains.  Possible 
discomforts and risks of the testing procedures include: 
• The radiation exposure in this study is thought to be minor. However, the effects of 
radiation add up over your lifetime. Repeated exposures may increase your risk of 
injury or disease. When deciding to enter this study you should consider previous 
and future potential exposures. Examples would include x-rays taken for a broken 
bone or radiation therapy treatments for cancer. Exposure to radiation during 
pregnancy can cause birth defects in unborn fetuses. Pregnant women should not 
undergo barium swallow procedures. 
• Barium will be the material used to help us see your swallow function and 
sometimes when testing is done the barium may enter your lungs during swallowing 
causing you to cough or feel some discomfort. While small amounts of barium 
ingested into the lungs does not pose a significant health risk, large amounts ingested 
over several days can lead to aspiration pneumonia, which is a bad respiratory 
infection. Therefore, we will stop the test if we see barium enter the airway on more 
than two swallows of liquid or food to prevent major health risk. 
 
This study may include risks that are unknown at this time. 
 
Throughout the study, the researchers will notify you of new information that may become 
available and might affect your decision to remain in the study. 
 
Will being in this research benefit me? 
The most important benefits that you may expect from taking part in this research include 
improvements in speech and swallowing functions. However, it is possible that you may not 
experience any improvement in speech or swallowing during the study period. 
 
Your participation, however, has the potential to help us better understand the impact of 
Nuedexta on speech and swallowing functions in patients with ALS. 
 
What are my responsibilities if I take part in this research? 
If you take part in this research, you will be responsible to take the study drug, Nuedexta, 
daily as prescribed and promptly report any side effects to the investigator 
 
Will it cost me money to take part in this research? 
The study drug will be prescribed and billed through your insurance company as standard of 
care. You will be responsible for any deductible, co-insurance, or co-payments. Some 
insurance companies may not cover costs associated with the study drug. 
 


IRB APPROVED 
AS MODIFIED 
Aug 21, 2019 
 
L. Tabor-Gray 
Protocol Version #2 
Page 7 of 10 
Version Date: 08/06/2019 
In some cases, insurance does not pay for services ordinarily covered because these services 
were performed in a research study. You should check with your insurance to see what 
services will be covered by your insurance and what you will be responsible to pay. 
 
What other choices do I have besides taking part in this research? 
This research is not designed to diagnose or prevent any disease. Your alternative is to not 
take part in the research. 
 
What happens to the information collected for this research? 
Your private information and your medical record will be shared with individuals and 
organizations that conduct or watch over this research, including: 
• The ALS Association 
• The Phil Smith ALS Clinic research team 
• Government agencies, such as the Food and Drug Administration 
• The Institutional Review Board (IRB) that reviewed this research 
• The University of Florida Research Team collaborating on this study 
 
We may publish the results of this research. However, we will keep your name and other 
identifying information confidential. 
 
We protect your information from disclosure to others to the extent required by law. We 
cannot promise complete secrecy. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site at 
any time. 
 
Data or specimens collected in this research might be deidentified and used for future 
research or distributed to another investigator for future research without your consent. 
 
Who can answer my questions about this research? 
If you have questions, concerns, or complaints, or think this research has hurt you or made 
you sick, talk to the research team at the phone number listed above on the first page. 
 
This research is being overseen by an Institutional Review Board ("IRB"). An IRB is a 
group of people who perform independent review of research studies. You may talk to them 
at (800) 562-4789, help@wirb.com if: 
• You have questions, concerns, or complaints that are not being answered by the 
research team. 
• You are not getting answers from the research team. 
• You cannot reach the research team. 
• You want to talk to someone else about the research. 
• You have questions about your rights as a research subject. 
 
What if I am injured because of taking part in this research? 
If you are injured or get sick because of being in this research, call the study doctor 
immediately. The study doctor will provide emergency medical treatment. Your insurance 


IRB APPROVED 
AS MODIFIED 
Aug 21, 2019 
 
L. Tabor-Gray 
Protocol Version #2 
Page 8 of 10 
Version Date: 08/06/2019 
may be billed for this treatment. No other payment is routinely available from the study 
doctor or sponsor. 
 
Can I be removed from this research without my approval? 
The person in charge of this research can remove you from this research without your 
approval. Possible reasons for removal include: 
• If it appears to be medically harmful to you 
• If you fail to follow directions for participating in the study 
• If it is discovered that you do not meet the study requirements 
• You are pregnant 
 
We will tell you about any new information that may affect your health, welfare, or choice 
to stay in this research. 
 
What happens if I agree to be in this research, but I change my mind later? 
You are free to withdraw your consent and to stop participating in this study at any time.  If 
you do withdraw your consent, you will not be penalized in any way and you will not lose any 
benefits to which you are entitled. 
 
If you decide to withdraw your consent to participate in this study for any reason, please 
contact one of the research team members.  They will tell you how to stop your participation 
safely. 
 
Will I be paid for taking part in this research?  
You will not be paid for taking part in this research.  
 


IRB APPROVED 
AS MODIFIED 
Aug 21, 2019 
 
L. Tabor-Gray 
Protocol Version #2 
Page 9 of 10 
Version Date: 08/06/2019 
Statement of Consent: 
I have been informed about this study's purpose, procedures, possible benefits and risks.  I 
have also been told alternatives to being in the study and how my protected health 
information will be collected, used, and shared with others.  I have been given the 
opportunity to ask questions.  My questions have all been answered satisfactorily.  I agree to 
be in this research study.  I have received a copy of this form. 
 
I authorize the confidential consultation of the study data including data collected about me 
by the organizations.  I also consent to video recordings of my swallowing during the 
swallowing exams. 
 
Commitment 
• I will attend all scheduled visits on time; 
• I will give true information about my medical history; 
• I will not participate in another clinical research study during this study beginning with 
the screening session until the end of the study; 
• I will respect all study restrictions and follow all instructions given to me by the study 
staff; 
• I will advise the study staff of any change in my medical condition, minor or major, 
during the study. 
 
Your signature documents your consent to take part in this research. 
 
 
 
 
 
 
 
Printed Name and Signature of Study Subject 
Date 
 
 
 
 
 
 
 
Printed Name and Signature of person obtaining consent 
Date 
 
 
 
 
 
 


IRB APPROVED 
AS MODIFIED 
Aug 21, 2019 
 
L. Tabor-Gray 
Protocol Version #2 
Page 10 of 10 
Version Date: 08/06/2019 
Attestation Statement 
 
I confirm that the research study was thoroughly explained to the subject.  I reviewed the 
consent form with the subject and answered the subject’s questions.  The subject appeared to 
have understood the information and was able to answer the following questions correctly:  
 
1. What is the purpose of this study?  
2. If you decide to be in the study, what will you be asked to do?  
3. What is the possible benefit of participating in this study? 
4. What are the possible risks of participating in this study?  
5. If you decide not to participate in this study, what options do you have?  
6. Will participating in this study cost you anything?  If so, what will you have to pay for?  
7. Do you have to be in this study? 
8. If you decide to be in the study, can you leave the study when you want to?  
 
 
________________________________________ 
__________________ 
Printed Name of Person Conducting the 
Position 
Informed Consent Discussion 
 
 
__________________________________________________________ 
Signature of Person Conducting the  
Date 
Informed Consent Discussion