Conditions: Parkinson Disease
Keywords: freezing of gait
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 21
Healthy volunteers: no

Brief summary:
Freezing of gait is a late stage complication of Parkinson's disease in which patients note that their feet feel stuck or glued to the ground. This can lead to imbalance and falls and the secondary complications that can result from falls such as fractures and hospitalizations. While levodopa can help freezing of gait in some patients, it does not help in all, and the dose needed to treat freezing may be limited by side effects of the medications. Currently there are no treatments targeted towards freezing of gait and the goal of this research is to see if Modafinil could be one such drug to help freezing of gait in Parkinson's disease.

Detailed description:
Freezing of gait is a late stage complication of Parkinson's disease in which patients note that their feet feel stuck or glued to the ground. This can lead to imbalance and falls and the secondary complications that can result from falls such as fractures and hospitalizations. While levodopa can help freezing of gait in some patients, it does not help in all, and the dose needed to treat freezing may be limited by side effects of the medications. Currently there are no treatments targeted towards freezing of gait and the goal of this research is to see if Modafinil could be one such drug to help freezing of gait in Parkinson's disease.

Approximately 20 subjects aged 18 or older with idiopathic Parkinson's disease with freezing of gait will be asked to enroll in the study from the patient population in the movement disorders clinic at the University of Arkansas for Medical Sciences (UAMS). Subjects will be assigned randomly 1:1 to an early start and delayed start arm of the study. In the early start arm subjects will receive 24 weeks of 50 mg oral daily Modafinil while subjects in the delayed start arm will receive 12 weeks of placebo followed by 12 weeks of 50 mg oral daily Modafinil. Assessments will be performed prior to initiation of medication at the screening visit, as well as at 12 weeks of the treatment phase. The assessments will include questionnaires to determine the frequency and severity of freezing of gait, level of mood, anxiety and apathy and quality of life, physical examination and tests of cognitive function. Objective assessment of patients walking will be conducted using a pressure sensor impregnated mat at each visit.

Arms:
arm 1: 24 weeks of modafinil 50 mg oral daily arm 2: 12 weeks of oral placebo followed by 12 weeks of modafinil 50 mg oral daily

Interventions: intervention 1: modafinil 50mg intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: 1 capsule oral daily intervention 2: 1 capsule oral daily

Protocol document:
Prot_SAP_001.pdf: 
 
 
 
 
Modafinil as a novel therapy for the treatment of 
freezing of gait in Parkinson’s disease  
 
 
 
NCT03083132  
 
 
 
June 28, 2017 
 


 
 
 
 
Study Title:  
Modafinil as a novel therapy for the treatment of freezing of gait in 
Parkinson’s disease 
 
Principal Investigator: 
Tuhin Virmani, MD, PhD 
University of Arkansas for Medical Sciences 
4301 W. Markham Street, Slot # 500 
Little Rock, AR 72205 
Telephone:  501-686-7235 
Fax: 501-686-8689 
Email:  TVirmani@uams.edu 
 
Sub-Investigator(s): 
Edgar Garcia-Rill, PhD 
 
 
 
 
Professor and Director 
 
 
 
 
Center for Translational Neuroscience 
 
 
 
 
Department of Neurobiology and Developmental Sciences 
 
 
Rohit Dhall, MD 
 
 
 
 
Associate Professor 
 
 
 
 
Department of Neurology 
 
 
 
 
 
Jennifer Kleiner-Fausett, PhD 
 
 
 
 
Associate Professor 
 
 
 
 
Department of Psychiatry 
 
 
Biostatistician: 
David Williams, PhD 
University of Arkansas for Medical Sciences 
4301 W. Markham Street, Slot # 781 
Little Rock, AR 72205 
Telephone:  501-526-6721 
Email:  WillamsDavidK@uams.edu 
 
Study Coordinator: 
 
Shannon Doerhoff, APRN 
 
 
 
 
Department of Neurology 
 
Medical Monitor: 
 
Mitesh Lotia, MD 
 
 
 
 
Assistant Professor 
 
 
 
 
Department of Neurology 
 
Study location(s): 
 
University of Arkansas for Medical Sciences, 5th floor JTS. 
 
Sponsor: 
 
 
UAMS 
 
Funding Source:  
UAMS Clinician Scientist Program 
 
CTN RFA (active May 1, 2017) 
 
Version No.: 
 
 
4 
 
Version Date: 
 
 
06/28/17 
 
 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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TABLE OF CONTENTS 
1.0 
LIST OF ABBREVIATIONS .................................................................................5 
2.0 
STUDY SUMMARY ...............................................................................................6 
3.0 
BACKGROUND AND RATIONALE ...................................................................7 
3.1 
Disease Background........................................................................................................ 7 
3.2 
Investigational Product Background ................................................................................ 7 
3.3 
Rationale .......................................................................................................................... 9 
4.0 
STUDY OBJECTIVES...........................................................................................9 
4.1 
Primary Objectives ........................................................................................................... 9 
4.2 
Secondary Objectives ...................................................................................................... 9 
4.3 
Exploratory Objectives ................................................................................................... 10 
4.4 
Endpoints ....................................................................................................................... 10 
5.0 
STUDY POPULATION ........................................................................................11 
5.1 
Inclusion Criteria ............................................................................................................ 11 
5.2 
Exclusion Criteria ........................................................................................................... 11 
5.3 
Accrual Goal .................................................................................................................. 12 
5.4 
Recruitment Plan ........................................................................................................... 12 
6.0 
INVESTIGATIONAL PRODUCT .......................................................................12 
6.1 
Test Article ..................................................................................................................... 12 
6.2 
Treatment Dosage and Administration .......................................................................... 13 
6.3 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 13 
6.4 
Concomitant Medications/Treatments ........................................................................... 14 
6.5 
Other Modalities or Procedures ..................................................................................... 14 
6.6 
Duration of Therapy ....................................................................................................... 14 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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6.7 
Duration of Follow Up .................................................................................................... 14 
6.8 
Removal of Patients from Protocol Therapy .................................................................. 14 
6.9 
Patient Replacement ..................................................................................................... 14 
7.0 
STUDY PROCEDURES ......................................................................................14 
7.1 
Screening/Baseline Procedures .................................................................................... 14 
7.2 
Procedures During Treatment ....................................................................................... 15 
7.3 
Schedule of Time and Events Table .............................................................................. 17 
7.4 
Removal of Subjects from Study ................................................................................... 18 
8.0 
Outcome Measures ............................................................................................18 
8.1 
Improvement in FOG ..................................................................................................... 18 
9.0 
ADVERSE EVENTS ............................................................................................20 
9.1 
Experimental Therapy.................................................................................................... 20 
9.2 
Adverse Event Monitoring ............................................................................................. 22 
9.3 
Definitions ...................................................................................................................... 23 
9.4 
Steps to Determine If an Adverse Event Requires Expedited Reporting ...................... 24 
9.5 
Reporting Requirements for Adverse Events ................................................................ 24 
9.6 
Unblinding Procedures .................................................................................................. 25 
9.7 
Stopping Rules .............................................................................................................. 25 
10.0 
STATISTICAL CONSIDERATIONS .............................................................25 
11.0 
STUDY MANAGEMENT .................................................................................25 
11.1 
Institutional Review Board (IRB) Approval and Consent ............................................... 26 
11.2 
Data Management and Monitoring/Auditing .................................................................. 26 
11.3 
Adherence to the Protocol ............................................................................................. 26 
11.4 
Amendments to the Protocol ......................................................................................... 26 
11.5 
Record Retention ........................................................................................................... 26 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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11.6 
Dissemination of data .................................................................................................... 27 
11.7 
Obligations of Investigators ........................................................................................... 27 
12.0 
REFERENCES .................................................................................................27 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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1.0 
LIST OF ABBREVIATIONS 
AE: Adverse Event 
AES-S: Apathy evaluation scale 
CBGD: Corticobasal ganglionic degeneration 
CBS: Corticobasal Syndrome 
DBS: Deep Brain Stimulators 
ET: Essential tremor 
FAB: Frontal Assessment Battery 
FOG: Freezing of gait 
FOG-Q: Freezing of gait questionnaire 
MoCA: Montreal cognitive assessment  
MSA: Multiple systems atrophy 
PAGF: Primary akinesia with gait freezing 
PD: Parkinson’s disease 
PDQ-39: Parkinson’s disease questionnaire for quality of life  
PKMAS: Protokinetic movement analysis software 
PPFG: Primary progressive freezing of gait 
PPN: Pedunculopontine nucleus 
PSP: Progressive supranuclear palsy 
RBD: Rapid eye movement sleep behavior disorder 
SCOPA-COG: Scales for outcome in Parkinson’s disease – cognition  
SSRIs: selective serotonin reuptake inhibitors 
SWS: stand-walk-sit 
TCAs: tricyclic antidepressants 
UPDRS: Unified Parkinson’s Disease Rating Scale 
 
 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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2.0 
STUDY SUMMARY 
Title 
Modafinil as a novel therapy for the treatment of freezing of gait in 
Parkinson’s disease 
Short Title 
Modafinil for FOG 
Protocol Number 
MODFOG01 
Phase 
Pilot, feasibility 
Methodology 
Randomized, placebo-controlled delayed start 
Study Duration 
1 year 
Study Center(s) 
Single-center 
Objectives 
Safety and efficacy of Modafinil for the treatment of freezing of gait in 
Parkinson’s disease 
Number of Subjects 
Enrolling 25 for a total of 20  
Diagnosis and Main 
Inclusion Criteria 
Idiopathic Parkinson disease with freezing of gait on stable Parkinson 
disease treatment for 3 months. 
Study Product(s), Dose, 
Route, Regimen 
Modafinil 50 mg capsule oral daily, Placebo capsule oral daily 
Duration of administration 
24 weeks (early-start), 12 weeks (delayed-start) 
Reference therapy 
none 
Statistical Methodology 
The study is a prospective repeated measures longitudinal design.  A 
primary statistical goal is to estimate the mean response at all six time 
points for each group and subsequently estimate changes in the 
outcome measures for each study group from baseline. 
 
 
 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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3.0 
BACKGROUND AND RATIONALE 
3.1 
Disease Background 
Patients with Parkinson Disease (PD) typically present with bradykinesia, rigidity, and 
frequently resting tremor along with other hallmarks such as shuffling gait, decreased 
blinking, decreased arm swing, hypophonia, hypomimia, micrographia, and decreased 
smell and taste.  In the later stages of the disease, dementia, postural instability, and 
freezing of gait are also common. Freezing of gait (FOG) is one of the more debilitating 
motor complications of PD.1, 2  It is manifested by the feet “sticking to the ground” for 
several seconds during active movement. FOG occurs initially when the patient is turning 
or when initiating gait (start-hesitation).  Later, it occurs when the patient reaches a 
destination, such as a chair, and the patient stops too soon, before fully reaching the 
desired destination. 
FOG is a complex disorder that can also be seen as an entity of its own in primary 
progressive freezing of gait (PPFG), primary akinesia with gait freezing (PAGF), or in 
atypical Parkinsonism such as vascular Parkinsonism, progressive supranuclear palsy 
(PSP), corticobasal syndrome (CBS), and multiple systems atrophy (MSA).  FOG has 
been thought to be due either to a variant in the disease process in certain individuals, or 
potentially as a side effect of levodopa, one of the mainstay medications used to treat the 
symptoms of PD.  Earlier onset FOG has been associated with earlier onset of 
dyskinesias and postural instability, the presence of hallucinations and greater 
neocortical Lewy Body burden.3 FOG in PD can occur both as a phenomenon of the 
“OFF state” which improves with addition of dopaminergic medications (i.e., either 
levodopa or dopamine agonists), but in an unknown percentage it also occurs in the “ON 
state” and does not respond to increased levodopa.  In fact FOG in the “ON state” is 
often reported to worsen with incrementally higher levodopa doses.  
The presence of gait freezing results in a significant worsening of quality of life for 
patients. Freezing leads to decreased mobility, increased rates of falls, and subsequent 
fear of falling, which further limits mobility.4-6  Morbidity associated with hip fractures from 
falls leads to hospitalizations, surgeries and further dependence on caregivers. Often, 
patients lapse into a wheelchair- or home-bound state, increasing pressure on care 
givers.  While OFF state FOG usually responds to increases in levodopa dosing, ON 
state FOG does not, and can even worsen.7  
Unfortunately, no good alternative treatments exist for FOG. Methylphenidate, a stimulant 
used in the treatment of Attention deficit hyperactivity disorder, inhibits presynaptic 
dopamine8 and the noradrenaline transporter. Used at high doses (1 mg/kg/day), 
methylphenidate has been shown to decrease the number of steps taken by PD patients 
who have undergone subthalamic nucleus (STN) DBS in the stand-walk-sit (SWS) test, 
but it has not been widely adopted due to cardiac side effects.9 Therefore, we will test 
whether another stimulant, Modafinil, could serve as a novel treatment for FOG. 
3.2 
Investigational Product Background  
The pedunculopontine nucleus (PPN) is a part of the reticular activating system, and 
arousing stimuli simultaneously activate ascending projections to the intralaminar 
thalamus triggering high frequency cortical activity, and descending projections to the 
reticulospinal systems altering posture and locomotion. This has led to the PPN being 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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used as a target for deep brain stimulation (DBS) in the treatment of PD, and proposed 
as a potential target for treating FOG in PD.10-12 PPN neurons fire at beta/gamma 
frequencies during waking and REM sleep but not during slow wave sleep.13 These 
oscillations are mediated by high threshold voltage dependent N- and P/Q-type calcium 
channels.14 Garcia-Rill and colleagues have shown that beta/gamma oscillations in PPN 
neurons were blocked by KN-93 (a CAMKII activation inhibitor), which suggests that at 
least some cells produce oscillations through the CAMKII pathway.   
Modafinil, a stimulant approved by the FDA for treatment of narcolepsy (decreases 
daytime sleepiness and regulates sleep-wake cycles), has a number of putative sites of 
action.15 Garcia-Rill and colleagues, as well as a group of researchers at NYU have both 
shown that modafinil works by increasing neuronal electrical coupling, and this action of 
modafinil is also modulated by the CAMKII pathway as KN-93 also inhibits the effects of 
modafinil.16, 17  Modafinil has also been shown to bind to the dopamine transporter and 
prevent dopamine reuptake, increasing the level of dopamine in the synaptic cleft.18  
Modafinil is a 1:1 racemic compound whose enantiomers have different pharmacokinetics 
(The half-life of R-modafinil is approximately three times that of S-Modafinil in humans). 
The effective elimination half-life of Modafinil is about 15 hours with linear kinetics upon 
multiple dosing of 200-600 mg/day with steady state reached after 2-4 days of dosing for 
narcolepsy.  Modafinil is absorbed orally with peak plasma concentrations in 2-4 hours. 
The major route of elimination is metabolism (approximately 90%) by the liver with 
subsequent renal elimination of metabolites.  In-vitro data suggests that Modafinil is a 
weak inducer of CYP3A activity in a concentration dependent manner and therefore may 
reduce the effectiveness of drugs that are substrates for CYP3A enzymes (e.g. steroidal 
contraceptives, cyclosporine, midazolam, triazolam). Data also suggest that Modafinil is a 
weak inducer of CYP1A2, CYP2B6, and CYP2C9 (warfarin and phenytoin). Modafinil is 
also a reversible inhibitor of CYP2C19 and therefore may increase concentrations of 
drugs metabolized by this enzyme (e.g. phenytoin, diazepam, propranolol, omeprazole, 
and clomipramine). Modafinil may interact with some CNS active drugs that PD patients 
may be using including certain tricyclic antidepressants (TCAs) (metabolized by 
CYP2C19) and selective serotonin uptake inhibitors (SSRIs) (metabolized by CYP2D6). 
Also concomitant administration of quetiapine reduced the systemic exposure of 
quetiapine. 
Based on data from the Garcia-Rill lab and a prior unpublished trial at the Little Rock VA 
on Modafinil in PTSD patients, subjects were found to be more jittery at doses of 100mg 
and higher (unpublished, personal communication). Therefore for this study low dose 
Modafinil at 50 mg orally daily will be trialed (the FDA approved recommended dosing for 
Narcolepsy is 200 mg/day for Narcolepsy). Additionally small studies in elderly 
populations suggest decreased clearance of Modafinil in elderly populations. One study 
showed approximately 20% decrease in oral clearance in 12 subjects given a single dose 
of 200 mg modafinil (mean age 63 years, range 53-72 years), while a study with multiple 
doses of 300 mg/day Modafinil in 12 subjects (mean age 82 years, range 67-87 years) 
showed mean plasma levels were two times those in historical younger subjects.  
 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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3.3 
Rationale 
FOG is present in approximately 60% of patients with PD and is a major cause of gait 
impairment leading to falls, and the morbidity and decreased quality of life. Currently, 
other than levodopa therapy, which can be limited in later stages of disease when FOG 
occurs by dose dependent side effects, no alternative treatments exist. Modafinil, as 
described above, has been shown by the Garcia-Rill lab to modulate pathways in the 
PPN that link arousal and gait dynamics. Additionally, PPN DBS has also been shown to 
modulate gait and falls in patients. As such, we propose to study whether Modafinil can 
improve FOG in PD. For this pilot study, we will focus on recruiting PD patients with FOG 
and use a delayed start trial model to determine whether FOG improves compared to 
placebo. We chose the delayed start trial model as opposed to just having a placebo arm 
as it will likely help with recruitment and subject retention if all subjects know that at least 
during 3 months of the trial they will all be receiving active drug.  Additionally, preliminary 
data (unpublished, UAMS IRB#203234) from my lab suggests that PD patients with FOG 
have a faster rate of decline in objective gait parameters compared to PD patients, even 
over a period of 3-6 months. Therefore, with the delayed start model we will also 
determine if there are any changes in the slope of decline in PD-FOG patients over the 
period of the trial. 
4.0 
STUDY OBJECTIVES 
 
This is a single-center, prospective, randomized, double-blinded, placebo-controlled, delayed-
start pilot trial involving up to 25 subjects with PD and FOG. Subjects will be randomized 1:1 to 
early start (24 weeks active treatment) or delayed start (12 weeks placebo followed by 12 weeks 
active treatment) oral Modafinil 50 mg/day.  Following 24 weeks of treatment, a 2 week washout 
of the drug will be performed with a follow-up assessment at 26 weeks.  
4.1 
Primary Objectives 
4.1.1 
To determine if 50 mg/day Modafinil decreases FOG in PD patients with FOG 
compared with placebo as measured by the Giladi Freezing of gait questionnaire 
(FOG-Q). 
4.1.2 
To determine if 50 mg/day Modafinil decreased the decline stride length seen in 
PD patients with FOG. 
 
4.2 
Secondary Objectives  
4.2.1 
To determine if 50 mg/day Modafinil improves motor function in PD patients with 
FOG compared to placebo as measured by the UPDRS Part III motor subscale.  
4.2.2 
To describe the adverse events associated with Modafinil dosed at 50 mg/day for 
3-6 months in PD patients. 
4.2.3 
To determine if quality of life is improved with Modafinil as measured by the 
PDQ-39. 
4.2.4 
To determine if sleep disorders are improved with Modafinil as measured by the 
RBD scale and Epworth Sleepiness Scale. 
 
 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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4.3 
Exploratory Objectives 
4.3.1 
To determine if Modafinil 50 mg/day improves cognitive function in PD patients 
with FOG compared to placebo as measured by the Montreal Cognitive 
assessment, Stroop test, Frontal Assessment Battery and Scales for Outcome in 
Parkinson disease, Cognitive assessment (SCOPA-cog) 
4.4 
Endpoints 
4.4.1 
Primary Endpoints 
4.4.1.1 
To determine if 50 mg/day Modafinil decreases freezing of gait in PD 
patients with FOG compared with placebo as measured by the Giladi 
Freezing of gait questionnaire (FOG-Q) after 12 weeks of active 
treatment or placebo. Subjects who drop out of the study after at least 
6 weeks of either treatment arm will be included in this analysis. 
4.4.1.2 
To determine if 50 mg/day Modafinil decreased the decline stride 
length seen in PD patients with FOG. The rate of decline in stride 
length will be compared plotting the stride length at steady state in 
subjects in the early and late-start arms to determine if the rate of 
decline improves in subjects taking Modafinil in the early-start arm 
and whether this rate of decline also improves in the second phase of 
the trial in the delayed-start arm.  
We will also determine if at the completion of 24 weeks, the early-start 
arm has differential change in slope of other continuous gait 
parameters (stride width, gait cycle time, gait cycle velocity, swing and 
stance percent, total single and double support time, cadence) 
compared to the delayed start arm suggesting that Modafinil slows the 
progression of the gait decline. 
 
4.4.2 
Secondary Endpoints  
4.4.2.1 
To determine if 50 mg/day Modafinil improves motor function in PD 
patients with FOG compared to placebo as measured by the UPDRS 
Part III motor subscale after 12 weeks of active treatment or placebo. 
Subjects who drop out of the study after at least 6 weeks of either 
treatment arm will be included in this analysis.  
4.4.2.2 
To describe the adverse events associated with Modafinil dosed at 50 
mg/day in patients treated for 3 months (delayed start arm) and 6 
months (early start arm) in Parkinson’s disease patients. 
4.4.2.3 
To determine if quality of life is improved with Modafinil as measured 
by the PDQ-39 after 12 weeks of active treatment or placebo. 
Subjects who drop out of the study after at least 6 weeks of either 
treatment arm will be included in this analysis. 
4.4.2.4 
To determine if sleep disorders are improved with Modafinil as 
measured by the RBD scale and Epworth Sleepiness Scale after 12 
weeks of active treatment or placebo. Subjects who drop out of the 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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study after at least 6 weeks of either treatment arm will be included in 
this analysis. 
 
 
4.4.3 
Exploratory Endpoints 
4.4.3.1 
To determine if Modafinil 50 mg/day improves cognitive function in PD 
patients with FOG compared to placebo as measured by the Montreal 
Cognitive assessment, Stroop test, Frontal Assessment Battery and 
Scales for Outcome in Parkinson disease, Cognitive assessment 
(SCOPA-cog) after 12 weeks of active treatment or placebo. Subjects 
who drop out of the study after at least 6 weeks of either treatment 
arm will be included in this analysis. Additionally we will determine if 
at the end of 24 weeks, whether the early-start group had additional 
benefit of the additional 12 weeks of Modafinil treatment. 
 
5.0 
STUDY POPULATION 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria 
to be enrolled in the study. Study treatment may not begin until a subject is enrolled. 
5.1 
Inclusion Criteria 
 
• 
Age ≥ 50 years. 
• 
Diagnosis of idiopathic PD on UK brain bank criteria. 
• 
Presence of FOG based on objective assessment by the movement disorders 
neurologist. 
• 
FOG-Q score > 8. 
• 
Stable PD therapy (including medications and stimulation) for a period of 3 months 
prior to trial enrollment. 
• 
Women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study 
entry, for the duration of study participation, and for 90 days following completion of 
therapy. Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician immediately. 
 
o 
A female of child-bearing potential is any woman (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by choice) 
who meets the following criteria: 
 
▪ 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
 
▪ 
Has not been naturally postmenopausal for at least 12 consecutive 
months (i.e., has had menses at any time in the preceding 12 
consecutive months). 
 
• 
Ability to understand and the willingness to sign a written informed consent. 
5.2 
Exclusion Criteria 
• 
Patients on antidopaminergic medications for a period of less than 1 year from date 
of enrollment. 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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• 
Patients who may require adjustment of their PD medications over the 6 month 
period of the trial. 
• 
History of allergic reactions to Modafinil or armodafinil. 
• 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, mitral valve prolapse, left ventricular hypertrophy, chronic obstructive 
pulmonary disease, known malabsorption syndromes, renal disease or hepatic 
disease, or psychiatric illness/social situations that would limit compliance with study 
requirements. 
• 
Individuals who are pregnant or breastfeeding 
• 
Non-english speaking individuals who are unable to complete the questionnaires and 
other assessments in English and/or follow instructions in English. 
 
5.3 
Accrual Goal 
The goal for this study is to complete 20 subjects with PD and FOG, randomized 1:1 to 
early start and delayed start with Modafinil.  Up to 25 patients may be enrolled in order to 
accomplish the goal. 
5.4 
Recruitment Plan 
Subjects will be recruited from the population of patients already performing routine gait 
assessments as part of an ongoing IRB by the PI (Dr. Virmani; UAMS IRB # 203234). In 
addition subjects will be recruited from the PI’s clinic patient population and from the two 
other movement disorders neurologists at UAMS (Dr. Lotia and Dr. Dhall). 
 
6.0 
INVESTIGATIONAL PRODUCT 
6.1 
Test Article 
Modafinil 
For this study Modafinil 50 mg oral capsules will be produced and dispensed by the 
UAMS pharmacy in gelatin capsules with microcrystalline cellulose as filler. Subjects will 
take Modafinil 50 mg capsule oral daily for either 12 weeks or 24 weeks depending upon 
whether they are in the early-start or delayed-start arm of the trial as described below 
(see Figure 1). 
Placebo 
For this study placebo capsules will be made of gelatin capsules filled with 
microcrystalline cellulose and will be identical to the Modafinil capsule. Subjects in the 
delayed start arm will receive 12 weeks of placebo followed by 12 weeks of Modafinil 50 
mg oral daily (see Figure 1) 
 
6.1.1 
Dispensing 
Modafinil and placebo capsules will be produced and dispensed by the pharmacy 
in labeled packets with appropriate instructions on how they should be taken. 
Both will be dispensed by the UAMS pharmacy in 6 week increments at study 
visits 1-4.  


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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6.1.2 
Treatment Compliance 
A pill diary will be provided to the patients in order to try and ensure compliance 
with the treatment regimen. Patients will also be asked to return the pill 
containers at each visit to help ensure compliance. If patients are unable to 
provide the pill diary then they will be asked to sign a form stating their 
compliance with the study dosing regimen. 
6.2 
Treatment Dosage and Administration 
 
The research pharmacy will create a randomization log, randomizing 20 subjects 1:1 to 
early start or delayed start modafinil (Figure 1). Subjects will be assigned the next line in 
the log in order of treatment. Subjects in the early-start arm will receive Modafinil 50 mg 
oral daily (a.m.) for 24 weeks while subjects in the delayed-start arm will receive oral 
placebo for the first 12 weeks of active treatment followed by Modafinil 50 mg oral daily 
for weeks 13-24 of the active treatment period. The drug will be washed out for a 2 week 
period with repeat assessments to determine any withdrawal symptoms. 
 
 
6.3 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity as described in section 9. If 
patients develop the following toxic side effects to Modafinil 50 mg (current FDA dosing 
for narcolepsy is 4 times this dose at 200 mg), they will be withdrawn from the study. 
 
• 
Stevens-Johnson Syndrome 
• 
Angioedema and Anaphylaxis 
• 
multi-organ failure 
• 
persistent excessive daytime sleepiness 
• 
psychiatric symptoms (any out of mania, delusions, suicidal ideations, 
paranoid delusions, or auditory hallucinations) 
• 
cardiovascular events (chest pain, palpitations, dyspnea, ischemic T-wave 
changes on electrocardiogram) 
 
 
Figure 1: Delayed-start trial model with 1:1 randomization into an early-start arm with 10 
subjects receiving Modafinil 50 mg oral daily for 24 weeks and 10 subjects randomized to 
a delayed-start arm receiving placebo for the 1st 12 weeks followed by Modafinil 50mg oral 
daily for weeks 13-24. Visits will be performed at initiation and randomization, followed by 
6, 12, 18 and 24 week visits in the active phase with the final visit performed after a 2 week 
drug washout phase. 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
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Missed doses will be tabulated using a pill diary and if more than 14 days of dosing was 
missed in either the first 12 weeks or the second 12 weeks of the active treatment phase 
then this would warrant removal of the patient from the study. 
6.4 
Concomitant Medications/Treatments 
All antidopaminergic agents (including typical and atypical antipsychotics, 
antidopaminergic antiemetics and antidopaminergic antidepressants) are restricted 
during the period of this trial and would in any case be contraindicated for use in patients 
with Parkinson disease. 
6.5 
Other Modalities or Procedures 
No other modalities (e.g., surgery, radiotherapy) or procedures (e.g., hematopoietic stem 
cell transplantation) will be used in the protocol treatment. 
6.6 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for a 
total of 24 weeks or until: 
• 
Disease progression is documented per the judgment of the investigator 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) (see section 6.3) 
• 
Patient decides to withdraw from the study, OR 
• 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
6.7 
Duration of Follow Up 
Patients will be reassessed at a 2 week follow-up visit after completion of the active 
treatment arm to determine if there are any adverse events associated with withdrawal of 
Modafinil 50 mg. As subjects will be recruited from the population of patients already 
cared for at the UAMS movement disorders clinic they may continue to get regular clinic 
visits at UAMS for the treatment of their Parkinson disease as determined by the 
movement disorders neurologist after the study period has elapsed. 
6.8 
Removal of Patients from Protocol Therapy 
Patients will be removed from therapy when any of the criteria listed in Section 7.4 apply. 
Notify the Principal Investigator, and document the reason for study removal and the date 
the patient was removed in the Case Report Form. The patient should be followed-up per 
protocol.  
6.9 
Patient Replacement 
Subjects who have completed less than 2 weeks of the active treatment arm may be 
replaced with an alternative subject who would be enrolled in the same treatment arm as 
the subject being replaced, i.e. either the early-start or delayed-start arm. Up to 25 
subjects may be recruited in order to try and obtain 20 subjects completing the study. 
7.0 
STUDY PROCEDURES 
7.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
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exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 14 days prior to registration unless 
otherwise stated. The screening procedures include: 
7.1.1 Informed Consent and HIPAA Authorization 
7.1.2 Medical history 
Complete medical and surgical history, and history of infections. Medical chart will 
be reviewed for potential contraindications to participation including available 
hepatic function tests, renal functions tests, and ECGs or echocardiograms if 
available. 
7.1.3 Demographics 
Age, gender, race, ethnicity 
7.1.4 Review subject eligibility criteria 
7.1.5 Review previous and concomitant medications 
7.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, orthostatic blood pressure), height, 
weight 
7.1.7 Adverse event assessment 
Baseline adverse events will be assessed. See section 9 for Adverse Event 
monitoring and reporting. 
7.2 
Procedures During Treatment 
Gait and Balance Assessments:  
Subjects will be asked to walk on the 20’ long by 4’ wide pressure sensor-impregnated 
Zeno Walkway using a number of protocols as outlined below. These assessments will 
be formed at enrollment, 6 weeks on Modafinil, 12 weeks on Modafinil and 2 weeks after 
stopping Modafinil. See Table 1 below for detailed study schedule. 
1. Walking at a comfortable pace on and off the mat, 8 lengths of the mat. 
2. Walking at a comfortable pace on and off the mat, 8 lengths of the mat, with two 
dual-task paradigms 
a. Texting on a cellular phone 
b. Counting backwards aloud from 250 
3. Walking at a comfortable pace making pivot turns on the mat, 8 lengths of the mat. 
4. Walking at a comfortable pace making U-turns turns on the mat, 8 lengths of the 
mat. 
5. Sit-Stand-Walk test: starting in a sitting position, standing up, walking to the end of 
the mat, pivot turn, walk back and sit back down, 4 repetition. 
6. Tandem walk the length of the mat 
7. Postural sway: stand with feet together for 30 seconds and then with feet in tandem 
for 30 seconds 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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8. Pull test: stand with examiner behind, pulling backwards at the shoulders at 4 
different strengths twice. 
a. First time asking the subject to step back only if needed 
b. Second time asking the subject to step back every time they get pulled 
 
Data from the Zeno Walkway will be collected using a desktop computer running the 
PKMAS software. The resulting data will be analyzed for standard characteristics of gait 
such as step time and length, stride time and length, stride velocity and acceleration, 
swing time, gait cycle time, center of pressure of each foot, center of body mass and 
coefficients of variation between these.  In addition, parameters of the episodic freezing 
episodes such as time to overcome the freeze, center of mass variation during the freeze 
and amplitude and frequency of tremor in the legs during the freezing episodes will also 
be captured and evaluated.   The program also provides raw data of every sensor 
reading during footfall allowing for a large number of additional parameters to be 
calculated and based on initial results, these parameters may be assessed in the future. 
The sensor data is time locked to two cameras to allow for accurate characterization of 
foot falls.  Subjects will be assessed in the OFF levodopa state and 60 minutes after 
taking their regularly prescribed levodopa dose at each time point.  
 
Additional assessments (See Table 1 below for detailed study schedule): 
The following measures/scales will be performed at every visit (unless otherwise 
specified) by Dr. Virmani (utilizing his protected clinical research time), or other study 
personnel: 
1. Demographic information will be recorded at screening/first visit (5 minutes). 
2. Complete neurological examination will be given every 12 weeks and at visit six 
(15 minutes). 
3. Vital Signs (orthostatic blood pressure and heart rate, weight) (5 minutes) 
4. Medication profile will be recorded or reviewed every visit (5 minutes).   
5. Complete movement disorders examination at every visit (10 minutes). 
6. Unified Parkinson’s Disease Rating Scale (UPDRS) (10 minutes).  
7. Freezing of gait questionnaire (FOG-Q) (or NFOG-Q) (2-3 minutes).  
8. Schwab and England Activities of Daily Living scale (1 minute).  
9. Hoehn and Yahr Scale Staging of Parkinson’s disease (no additional patient 
time).  
10. Epworth sleepiness scale (2-3 minutes).  
11. REM Sleep Behavior Disorder Screening Questionnaire (2-3 minutes).  
12. Apathy Evaluation scale (AES-S) (5 minutes).  
13. Parkinson’s disease questionnaire for quality of life (PDQ-39) (7-10 minutes).  
14. Montreal Cognitive Assessment (MoCA) every 12 weeks and at visit six (10-15 
minutes).  
15. Frontal assessment battery (FAB) every 12 weeks and at visit six (5-10 minutes).  


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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16. Stroop test every 12 weeks and at visit six (3-5 minutes).  
17. Scales for outcome in Parkinson’s disease – cognition (SCOPA-COG) every 12 
weeks and at visit six (10-15 minutes).  
7.3 
Schedule of Time and Events Table 
  
Activity 
Visit 1 
(Screening 
Visit) 
Visit 2 
(6 weeks) 
Visit 3  
(12 weeks) 
Visit 4  
(18 weeks) 
Visit 5  
(24 weeks) 
Visit 6  
(26 weeks) 
Inclusion/Exclusion 
X 
 
 
 
 
 
Informed Consent Signed 
X 
 
 
 
 
 
HIPAA Authorization 
Signed 
X 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
Vital Signs1 
X 
X 
X 
X 
X 
X 
Medication Profile1 
X 
X 
X 
X 
X 
X 
Complete Neurological 
Examination1 
X 
 
X 
 
X 
X 
Complete Movement 
Disorders Examination1 
X 
X 
X 
X 
X 
X 
Gait and Balance 
Measurements1 
X 
X 
X 
X 
X 
X 
Unified Parkinson’s 
Disease Rating Scale 
(UPDRS) 1 
X 
X 
X 
X 
X 
X 
Freezing of Gait 
Questionnaire (FOG-Q or 
NFOG-Q) 1 
X 
X 
X 
X 
X 
X 
Schwab & England 
Activities of Daily Living 
Scale1 
X 
X 
X 
X 
X 
X 
Hoehn & Yahr Scale 
Staging of Parkinson’s 
Disease1 
X 
X 
X 
X 
X 
X 
Montreal Cognitive 
Assessment  (MoCA) 1 
X 
 
X 
 
X 
X 
Frontal Assessment 
Battery (FAB)1 
X 
 
X 
 
X 
X 
Stroop Test1 
X 
 
X 
 
X 
X 
Scales for Outcome in 
Parkinson’s Disease – 
Cognition (SCOPA-COG) 
1 
X 
 
X 
 
X 
X 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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Epworth Sleepiness 
Scale2 
X 
X 
X 
X 
X 
X 
REM Sleep Behavior 
Disorder Screening 
Questionnaire2 
X 
X 
X 
X 
X 
X 
Apathy Evaluation Scale 
(AES-S)2 
X 
X 
X 
X 
X 
X 
Parkinson’s Disease 
Questionnaire for Quality 
of Life (PDQ-39)2 
X 
X 
X 
X 
X 
X 
1 Study staff performed 
2 Self-assessment questionnaires 
 
7.4 
Removal of Subjects from Study 
Patients can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
▪ 
Patient voluntarily withdraws from treatment (follow-up permitted); 
▪ 
Patient withdraws consent (termination of treatment and follow-up); 
▪ 
Patient is unable to comply with protocol requirements; 
▪ 
Patient demonstrates disease progression (unless continued treatment with 
study drug is deemed appropriate at the discretion of the investigator); 
▪ 
Patient experiences toxicity that makes continuation in the protocol unsafe; 
▪ 
Treating physician judges continuation on the study would not be in the patient’s 
best interest; 
▪ 
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
▪ 
Lost to follow-up. If a research subject cannot be contacted despite repeated 
attempts during the 6 month period they will be considered lost to follow-up. All 
attempts to contact the subject during the 6 months must be documented and 
approved by the Data Monitoring Committee. 
8.0 
Outcome Measures 
8.1 
Improvement in FOG 
8.1.1 
Motor assessments 
Giladi freezing of gait questionnaire (FOG-Q): Validated questionnaire with 6 
items rated 0-4 for a total of 24 points in total. We will be looking for a 10% 
change in this questionnaire to suggest a subjective improvement in freezing of 
gait over the course of the study. 
 
UPDRS Part III motor score: Validated rating scale used to quantify the 
movement disorders motor examination including items for bradykinesia, tremor, 
rigidity and gait.  
 
Gait and balance measures: Will evaluate for changes in steady state gait and 
balance measures using the assessments outlined in section 7.2 including mean 
and percent coefficient of variability in:  
• 
Stride length 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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• 
Stride width 
• 
Stride velocity 
• 
Step time 
• 
Step length 
• 
Gait cycle time 
• 
Swing cycle percent 
• 
Stance cycle percent 
• 
Single support percent 
• 
Total double support percent 
• 
Velocity 
• 
Cadence 
• 
Ambulation time 
8.1.2 
Cognitive assessments: 
The following cognitive assessments will be administered by Dr. Virmani or other 
trained study personnel. Dr. Kleiner-Fausett (licensed psychologist) will supervise 
the interpretation of these results. 
 
Montreal cognitive assessment (MoCA): commonly used scale to screen for 
cognitive dysfunction in Parkinson disease patients.  
 
Frontal assessment battery (FAB): commonly used scale to screen for frontal 
lobe dysfunction that can be suggestive of atypical parkinsonisms and also 
associated with frontal gait disorders that also have FOG.  
 
SCOPA-cog: cognitive rating scale used in European trials to track cognitive 
function in Parkinson disease patients.  
 
Stroop test: test of mental flexability and set shifting using colored words that 
FOG patients have been shown in some preliminary studies to have more 
difficulty with than PD without FOG patients. 
 
8.1.3 
Psychometric, sleep and quality of life scales 
Epworth sleepiness scale: scale commonly used in sleep medicine to evaluate 
daytime sleepiness in patients due to untreated (or undertreated) sleep apnea. 
As Modafinil has benefit in arousal, will track patients to see if they are reporting 
improved daytime sleepiness which could account for improved FOG if it 
occurred.  
 
REM sleep behavior disorder (RBD) screening questionaire: parasomnias are 
commonly reported in PD and RBD is a prominent non-motor feature that is 
thought to be a pre-motor symptoms of the disease. As reticular activating 
pathways play a role in sleep, this will be used as measure to see if sleep is 
altered by Modafinil through its putative role in the reticular activating system. 
 
Apathy evaluation scale (AES): Validated questionnaire to assess apathy in 
patients. Apathy has been reported as correlated with overall level of motor 
function and will be tracked to see if apathy improved with the treatment.  
 
PDQ-39: validated questionnaire to assess overall quality of life in PD patients 
and will be tracked to determine whether any objective improvement in FOG 
overall leads to improved subjective assessment of quality of life.  


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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8.1.4 
Other measures 
Schwab and England Activities of Daily Living Scale: subjective global 
percentage assessment of overall function of PD patients that will be tracked 
over the trial.  
 
Hoehn and Yahr scale staging of Parkinson’s disease:  staging scale, primarily 
developed for research based on unilateral, bilateral, postural stability and level 
of gait disability which will be tracked and requires no addition patient time, other 
than the UPDRS motor score above.  
 
 
 
9.0 
ADVERSE EVENTS 
9.1 
Experimental Therapy 
While Modafinil does not have an indication in the treatment of freezing of gait in 
Parkinson disease it is FDA approved for the treatment of narcolepsy and has had a 
number of small clinical trials for use on various psychiatric conditions (ex. Depression 
and PTSD) but also is commonly used off label for daytime sleepiness. It has also been 
previously tested in Parkinson’s disease patients with fatigue (total of 53 patients).19, 20 
For the most recent safety update, please refer to the commercially available drug insert 
for Modafinil (PROVIGIL). 
 
Modafinil has previously been FDA approved for use in patients with narcolepsy.  In 
clinical trials 151 protocol specified doses of up to 1600 mg/day have been administered 
to 32 subjects with no reported life-threatening events. Case reports of up to 4500 
mg/dose also have not reported life-threatening events but reported excitation, agitation, 
insomnia and moderate elevation in hemodynamic parameters.  
9.1.1 
Contraindications: 
• 
Allergic reaction to any of the ingredients 
• 
Have had a rash or allergic reaction to either Modafinil or armodafinil 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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9.1.2 
Special Warnings and Precautions for Use 
Modafinil is a controlled substance as it can be abused and/or lead to 
dependence. Keep in a safe place to avoid misuse and abuse.  
9.1.3 
In-vitro data suggests that Modafinil is a weak inducer of CYP3A activity in a 
concentration dependent manner and therefore may reduce the effectiveness of 
drugs that are substrates for CYP3A enzymes (e.g. steroidal contraceptives, 
cyclosporine, midazolam, triazolam). Data also suggest that Modafinil is a weak 
inducer of CYP1A2, CYP2B6, and CYP2C9 (warfarin and phenytoin). Modafinil is 
also a reversible inhibitor of CYP2C19 and therefore may increase 
concentrations of drugs metabolized by this enzyme (e.g. phenytoin, diazepam, 
propranolol, omeprazole and clomipramine). Modafinil may interact with some 
CNS active drugs that PD patients may be using including certain tricyclic 
antidepressants (TCAs) (metabolized by CYP2C19) and selective serotonin 
uptake inhibitors (SSRIs) (metabolized by CYP2D6). Also concomitant 
administration of quetiapine reduced the systemic exposure of quetiapine. A 
recent report of a large overdose did not result in serious harmful effects.21 
9.1.4 
Adverse Events:  
The following serious adverse reactions have been reported in the FDA approved 
label for Modafinil and will be monitored for including: 
• 
serious rash (0.8%) including Stevens-Johnson Syndrome 
• 
Angioedema and Anaphylaxis (one case reported out of 1595 patients) 
• 
multi-organ hypersensitivity reactions 
• 
persistent sleepiness 
• 
psychiatric symptoms (0.3% including: mania, delusions, suicidal ideations, 
paranoid delusions, auditory hallucinations with doses of 600 mg/day) 
• 
effect on ability to drive and use Machinery 
• 
cardiovascular events (chest pain, palpitations, dyspnea, ischemic T-wave 
changes on electrocardiogram [occurred in 3 subjects with mitral valve 
prolapse or left ventricular hypertrophy], one episode of 9-seconds of 
asystole in a 35 year-old obese narcoleptic male with a prior history of 
syncope on 300 mg/day modafinil) 
 
 
 
The following adverse reactions were reported in placebo controlled trials of 
Modafinil in Narcolepy, obstructive sleep apnea and shift work disorder in 1% or 
more of the modafinil treated group. 
 
modafinil (%) 
(n=934) 
placebo (%) 
(n=567) 
Headache 
34 
23 
Nausea 
11 
3 
Nervousness 
7 
3 
Rhinitis 
7 
6 
Back Pain 
6 
5 
Diarrhea 
6 
5 
Anxiety 
5 
1 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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Dizziness 
5 
4 
Dyspepsia 
5 
4 
Insomnia 
5 
1 
Anorexia 
4 
1 
Dry Mouth 
4 
2 
Pharyngitis 
4 
2 
Chest Pain 
3 
1 
Hypertension 
3 
1 
Abnormal Liver Function 
2 
1 
Constipation 
2 
1 
Depression 
2 
1 
Palpitation 
2 
1 
Paresthesia 
2 
0 
Somnolence 
2 
1 
Tachycardia 
2 
1 
Vasodilatation 
2 
0 
Abnormal Vision 
1 
0 
Agitation 
1 
0 
Asthma 
1 
0 
Chills 
1 
0 
Confusion 
1 
0 
Dyskinesia 
1 
0 
Edema 
1 
0 
Emotional Lability 
1 
0 
Eosinophilia 
1 
0 
Epistaxis 
1 
0 
Flatulence 
1 
0 
Hyperkinesia 
1 
0 
Hypertonia 
1 
0 
Mouth Ulceration 
1 
0 
Sweating 
1 
0 
Taste Perversion 
1 
0 
Thirst 
1 
0 
Tremor 
1 
0 
Urine Abnormality 
1 
0 
Vertigo 
1 
0 
 
9.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of Subjects enrolled in the studies as well as those 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
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who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial. Additionally, certain adverse events 
must be reported in an expedited manner to allow for optimal monitoring of subject safety 
and care.  
 
9.3 
Definitions 
9.3.1 Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a subject receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention.  
9.3.2 Severity of Adverse Events 
The severity of adverse events will be graded as follows: 
Mild: the event causes discomfort without disruption of normal daily activities. 
Moderate: the event causes discomfort that affects normal daily activities. 
Severe: the event makes the patient unable to perform normal daily activities or 
significantly affects his/her clinical status. 
9.3.3 Serious Adverse Events 
A “serious” adverse event is defined in regulatory terminology as any untoward 
medical occurrence that meets one or more of the following criteria: 
9.3.3.1 
Results in death. 
If death results from (progression of) the disease, the disease should 
be reported as event (SAE) itself. 
9.3.3.2 
Is life-threatening. 
(the patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were 
more severe). 


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9.3.3.3 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
9.3.3.4 
Results in persistent or significant disability or incapacity. 
9.3.3.5 
Is a congenital anomaly/birth defect 
9.3.3.6 
Is an important medical event 
9.3.3.7 
Any event that does not meet the above criteria, but that in the 
judgment of the investigator jeopardizes the patient, may be 
considered for reporting as a serious adverse event. The event may 
require medical or surgical intervention to prevent one of the 
outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in 
an emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency. 
9.4 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: Identify the adverse event.  
 
Step 2: Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
Step 3:  Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in: 
• 
the current known adverse events listed in the Agent Information Section of this 
protocol; 
• 
the drug package insert; 
 
Step 4:  Determine whether the adverse event is a Serious Adverse Event 
9.5 
Reporting Requirements for Adverse Events 
9.5.1 
Expedited Reporting 
• 
The Principal Investigator must be notified within 24 hours of learning of any 
serious adverse events, regardless of attribution, occurring during the study.  
• 
The IRB must be notified within 10 business days of any unanticipated 
problems involving risk to subjects or others” (UPIRTSO).  A UPIRTSO is 
defined as any problem, event or new information that is: 
1. Unanticipated or unexpected; 
2. Related to the research; and 
3. Involves new or increased risks to subjects or others. 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
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Sponsor:  UAMS 
 
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• 
The FDA should be notified within 7 business days of the PI learning of any 
unexpected fatal or life-threatening adverse event with possible relationship 
to study drug, and 15 business days of the Sponsor learning of any event 
that is considered: 1) serious, 2) unexpected, and 3) at least possibly 
related to study participation. 
9.5.2 
Routine Reporting 
• 
All other adverse events- such as those that are expected, or are unlikely or 
definitely not related to the study participation- are to be reported annually 
as part of regular data submission. 
9.6 
Unblinding Procedures 
Depending upon the AE or if there is a SAE or unforeseen event, the treatment of the 
subject may need to be unblinded as part of management of the event at the discretion of 
the PI. The IRB will be notified within 10 days of the unblinding and it will be documented 
in the subject’s source document. 
9.7 
Stopping Rules  
Dosing of a particular subject may be stopped prematurely by the principle investigator if 
the subject: 
1. Experiences an intolerable adverse event (see section 6.3);  
2. Develops a clinically significant laboratory or ECG abnormality; 
3. Develops an allergic or anaphylactoid reaction to the medication; 
4. The principal investigator consider that the number and/or severity of 
adverse events justify discontinuation of the study  
10.0 
STATISTICAL CONSIDERATIONS 
 
The study is a prospective repeated measures longitudinal design.  The primary outcome 
response is the FOG-Q total score and the stride length changes, and the secondary responses 
are the UPDRS Part III subscale, the PDQ-39, the RBD scale, and the Epworth Sleepiness Scale. 
These measures will be observed at 6 time points for both study arms. A primary statistical goal is 
to estimate the mean response at all six time points for each group and subsequently estimate 
changes in the outcome measures for each study group from baseline. Additionally, it is of 
interest to estimate the how the study groups differ in their mean change from baseline.  A two 
group repeated measures linear model will be employed to determine significance for within each 
group and then to compare among the groups. Significance will be declared at the 5% level of 
significance and Bonferroni methods will be used for multiple comparisons.  This analysis 
approach will be applied to the primary and secondary responses. 
 
The study calls for 10 subjects in both arms for a total of 20 patients. Within a study arm the linear 
model will have in excess of 80% power to detect a 1.75 unit difference in observed means.  
Based on standard deviation estimates from previous researchers in similar settings,22 the FOG-
Q (the primary response) has a standard deviation of 3.58. This implies that we will have power to 
detect a 6.265 (1.75*3.58) unit difference among time point means at the 5% level of significance. 
Power calculations are from ‘Tables of Sample Sizes in the Analysis of Variance’ published by 
Bratcher.23 
 
11.0 
STUDY MANAGEMENT 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
26 
Version No.: 4 
Date: 06/28/17 
11.1 
Institutional Review Board (IRB) Approval and Consent  
This study will be conducted in accordance with all applicable government regulations 
and University of Arkansas for Medical Sciences research policies and procedures.  This 
protocol and any amendments will be submitted and approved by the UAMS Institutional 
Review Board (IRB). 
 
The formal consent of each subject, using the IRB-approved consent form, will be 
obtained before that subject is submitted to any study procedure.  All subjects for this 
study will be provided a consent form describing this study and providing sufficient 
information in language suitable for subjects to make an informed decision about their 
participation in this study.  The person obtaining consent will thoroughly explain each 
element of the document and outline the risks and benefits, alternate treatment(s), and 
requirements of the study.  The consent process will take place in a quiet and private 
room, and subjects may take as much time as needed to make a decision about their 
participation.  Participation privacy will be maintained and questions regarding 
participation will be answered.  No coercion or undue influence will be used in the 
consent process.  This consent form must be signed by the subject or legally acceptable 
surrogate, and the individual obtaining the consent.  A copy of the signed consent will be 
given to the participant, and the informed consent process will be documented in each 
subject’s research record. 
 
The trial will be registered on clinicaltrials.gov in accordance with current guidelines. 
11.2 
Data Management and Monitoring/Auditing 
Paper data will be stored in a locked file cabinet in the PI’s (Dr. Virmani’s) office in the 
Spine building. Additionally, source paper documents will be routinely scanned and the 
electronic versions will be stored on a secure computer located in the gait lab, with 
access only to the PI, co-Investigators, other members of the research team and safety 
monitors including the medical monitor and the UAMS Office of Research Regulatory 
Affairs (ORRA) after IRB approval. Data auditing will be at the discretion of the UAMS 
IRB committee as needed. 
11.3 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  Investigators may only 
implement a deviation from or a change to the protocol to eliminate an immediate 
hazard(s) to subjects without prior IRB approval.   
11.4 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to the 
patient, a revised consent form might be required.  
 
The amended protocol, and if required the amended consent form, must be approved by 
the IRB prior to implementation.  
11.5 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, monitoring logs/letters, and regulatory documents (e.g., protocol and 
amendments, IRB correspondence and approval, signed patient consent forms).  All 


Study Title: Modafinil for FOG (UAMS IRB#206341) 
PI: Tuhin Virmani, MD, PhD 
Sponsor:  UAMS 
 
27 
Version No.: 4 
Date: 06/28/17 
study records will be retained in accordance with applicable institutional and applicable 
regulatory requirements. 
 
11.6 
Dissemination of data 
Results of this study may be used for presentations, posters, or publications. The 
publications will not contain any identifiable information that could be linked to a 
participant but can contain sample videos after the use of video editing software to mask 
identifying facial features. 
 
11.7 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with applicable regulatory requirements. The Principal Investigator is 
responsible for personally overseeing the treatment of all study subjects. The Principal 
Investigator must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all applicable regulations 
and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator will be responsible for assuring that all the required data will be 
collected and entered onto the Case Report Forms and these will be reviewed 
continually. Periodically, monitoring visits will be conducted by ORRA monitors and the 
Principal Investigator will provide access to his/her original records to permit verification 
of proper entry of data. At the completion of the study, all case report forms will be 
reviewed by the Principal Investigator and will require his/her final signature to verify the 
accuracy of the data. 
12.0 
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Sponsor:  UAMS 
 
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Date: 06/28/17 
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