Informing Treatment Decisions in the Central Disorders of Hypersomnolence: A Pragmatic Clinical Trial of Modafinil Versus Amphetamines
Phase: PHASE2
Conditions: Idiopathic Hypersomnia, Narcolepsy Without Cataplexy
Sponsor: Emory University

Study Protocol 
 
Title: Informing Treatment Decisions in the Central Disorders of 
Hypersomnolence: A Pragmatic Clinical Trial of Modafinil Versus 
Amphetamines 
 
NCT Number: NCT03772314 
 
Protocol date: September 25, 2020 

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TITLE: Informing Treatment Decisions in the Central Disorders of Hypersomnolence: 
A Clinical Trial of Modafinil Versus Amphetamines
Short Title: A Clinical Trial of Modafinil Versus Amphetamines
PI: Lynn Marie Trotti, MD, MSc, Associate Professor of Neurology
Funder: American Association of Sleep Medicine Foundation
Protocol Version: 8.0
Protocol Date: 9/25/2020

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Abstract
Currently, there are insufficient data to guide clinical practice regarding the use of amphetamines for the 
treatment of narcolepsy.  This may be particularly important in the case of narcolepsy type 2, for which 
randomized, controlled trial data show that other treatments are less beneficial than they are for participants 
with narcolepsy type 1.  For the closely related disorder of idiopathic hypersomnia, clinical trial data to guide 
treatment decision-making are even more limited, with only three published controlled trials ever performed.
To address these evidence gaps, we propose a randomized, active-treatment controlled trial comparing 
modafinil and amphetamine salts for the treatment of narcolepsy type 2 and idiopathic hypersomnia.  The 
primary outcome will be reduction in excessive daytime sleepiness, as measured by change in Epworth 
Sleepiness Scale scores from baseline to week 12 on treatment.  Other important patient-reported outcomes will 
be considered as secondary outcomes, including Patient Global Impression of Change for sleep inertia, 
cognitive dysfunction, and sleepiness.  
In addition to directly comparing the efficacy of these two medications for hypersomnolent patients, this 
study will also evaluate for relatively safety in this population.  Further, we will assess for clinical predictors of 
treatment response.  All three of these aims will be complementary in informing shared decision-making about 
whether to treat with modafinil or amphetamine salts.    
Background
Current evidence-based treatment guidelines for narcolepsy from the American Academy of Sleep 
Medicine (AASM) give the highest level of recommendation to modafinil and sodium oxybate, with a lower 
level of evidence supporting use of methylphenidate and amphetamine-based stimulants (1).  Despite this lower 
level of evidence in support of their benefit, central nervous stimulants are widely used in clinical practice.  
Very few data are available to guide clinical decision-making regarding which medication should be prescribed 
for which patient with narcolepsy.  
Most clinical trials for narcolepsy have combined participants with types 1 and 2, despite the known 
difference in underlying pathophysiology of these disorders (2).  Post-hoc analyses have suggested that there are 
important differences in treatment response between participants with these two distinct disorders, with patients 
with narcolepsy type 2 significantly less likely to achieve “much improved” or “very much improved” status on 
the Clinical Global Impression of Change scale in modafinil and sodium oxybate trials (3).  In contrast to 
narcolepsy type 1, which has a distinct phenotype and well-characterized pathophysiology of hypocretin 
neuronal loss, idiopathic hypersomnia is much more closely related to narcolepsy type 2.  The clinical features 
of narcolepsy type 2 and idiopathic hypersomnia are so similar that diagnosis-independent cluster analysis sorts 
patients with these two disorders into the same cluster, which is distinct from those patients with narcolepsy 
type 1 (4).  The multiple sleep latency test is the only tool that can distinguish these disorders, but patients with 
narcolepsy type 2 and idiopathic hypersomnia frequently change diagnostic categories on repeat testing (5-7).  
Finally, although the causes of both narcolepsy type 2 and idiopathic hypersomnia are currently unknown, 
emerging data suggest a possible shared pathophysiology (8).  
Data to guide clinical practice for patients with idiopathic hypersomnia are even more sparse than for 
patients with narcolepsy type 2.  To date, only three randomized controlled trials of any medication for 
idiopathic hypersomnia have been published (9-11).  None of these trials investigated amphetamine-based 
stimulants, whose use in idiopathic hypersomnia is supported only by very small patient series (12).  Further, no 
treatments are currently recognized by the US FDA for the treatment of idiopathic hypersomnia.  This lack of 
data complicates shared decision-making and frequently results in the denial of medication coverage, severely 
limiting treatment options.  

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Although explanatory, randomized, placebo-controlled trials (RCTs) are the gold-standard for assessing 
efficacy, they are frequently insufficient to guide clinical practice because of narrow inclusion/exclusion criteria 
and comparison to a placebo rather than to a real-world clinical alternative (13, 14).  Patients with comorbid 
conditions are frequently excluded from clinical trials [e.g., (10, 15)], despite a high rate of comorbidity in 
patients with narcolepsy (16), limiting generalizability of results.  Furthermore, enrollment in a traditional 
explanatory RCT is limited to those patients whose symptom severity is such that they can commit to a placebo 
treatment for the duration of the study, should they be randomized to that arm.  This excludes many patients 
who are seen in clinical practice, whose disease severity is such that use of a placebo is untenable, because of 
the impacts of untreated excessive daytime sleepiness on ability to work, drive, and maintain family obligations 
(17, 18).  This further limits the generalizability of explanatory RCTs to those patients with relatively mild 
disease manifestations.  Finally, use of a placebo comparator does not guide decision-making between two 
different active treatments, which is the type of information needed in clinical practice.
In contrast, trials that incorporate degrees of pragmatism (19, 20) can help overcome some of these 
obstacles to increase generalizability and more clearly guide clinical practice.  Inclusion criteria are 
intentionally broad, allowing inclusion of patients with clinically-important comorbidities (e.g., mood disorders 
among narcolepsy patients), to better mimic the range of patients encountered in clinical practice (13, 20).  Two 
active treatments may be directly compared, rather than employing a placebo (13), so that patients considering 
enrollment can be assured that they will receive an active treatment for the duration of the study.  The majority 
of measures collected are those that can be embedded into clinical practice (20).  
Pragmatic trials also emphasize the use of outcomes that are important to patients (20).  To date, RCTs 
for the central disorders of hypersomnolence have predominantly focused on excessive daytime sleepiness.  
While this is undeniably the core symptom of these disorders, other symptoms may be equally or more 
problematic for patients.  Among people with narcolepsy in the Nexus Narcolepsy Registry, 57.1% cited 
difficulty concentrating, focusing, or thinking as a reason they initially sought medical evaluation for narcolepsy 
(21).  In an FDA-convened patient panel of patients with narcolepsy, chronic cognitive dysfunction was the 
aspect of excessive sleepiness that received the most attention, with participants endorsing “brain fog”, impaired 
alertness, decreased mental agility, and difficulty thinking (22).  We have been collaborating with the 
Hypersomnia Foundation, a national organization for people with hypersomnia disorders, to delineate the most 
important symptoms identified by these patients.  As of May 2018, 1077 participants with hypersomnia 
disorders had completed our questionnaire.  Limiting data to those 570 respondents with idiopathic 
hypersomnia or narcolepsy without cataplexy/type 2, it is clear that many respondents have persistent symptoms 
that are not being well-addressed by their current treatments.  Eighty percent experience daily or near-daily 
difficulty with morning sleep inertia, without a significant difference between those taking and not taking wake-
promoting medications (p = 0.65).  Fifty-two percent experience daily “brain fog”, again not different between 
those treated and not treated (p = 0.11).  Even among treated patients, 60% still experience daytime sleepiness 
(Trotti, unpublished data).  Taken together, these patient reported data highlight the need to evaluate all these 
symptoms when assessing for differential responses by treatment type.  
Objectives:
  To address the limitations in current evidence for the treatment of central disorders of 
hypersomnolence and better guide shared clinical decision-making, we propose a pragmatic clinical trial 
comparing modafinil and amphetamine salts in patients with narcolepsy type 2 or idiopathic hypersomnia.
Aim 1: To compare the effectiveness of modafinil and amphetamine salts in patients with narcolepsy 
type 2 or idiopathic hypersomnia.  The primary outcome will be the change in Epworth Sleepiness Scale score 
from pre-treatment baseline.  Secondary outcomes will include Patient Global Impression of Change from 
baseline for sleepiness, sleep inertia, and cognitive dysfunction.  

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Aim 2: To compare the safety of modafinil and amphetamine salts in the treatment of narcolepsy type 2 
or idiopathic hypersomnia.
Aim 3: To evaluate for clinical predictors of response to modafinil and amphetamine salts in these 
patients.  
Study Design & Methods  
Treatment-naïve adult patients (n = 44), or adult patients free of wake-promoting medication or willing 
to discontinue current wake-promoting medication seeking evaluation at the Emory Sleep Center for narcolepsy 
type 2 or idiopathic hypersomnia will be invited to participate and randomized to one of the treatment arms 
upon consent. Although pragmatic trials often do not involve blinding to condition, those trials where outcomes 
of interest are primarily subjective often require blinding to minimize bias (20), which will be necessary in this 
case.  Randomization, allocation concealment, blinding, and medication dispensing will be managed by 
Emory’s Investigational Drug Service (IDS).  The IDS will use 1:1 computer generated randomization (23), 
with a block design to ensure equal number of participants receiving each study medication.  Block size will not 
be disclosed to the study investigators or staff.  Identity of medications will be concealed by the pharmacy using 
matched pills and pill containers.  The IDS is located in a separate building from the study team and will have 
no interaction with participants.  Medications will be transferred from the pharmacy via courier.  This protocol 
will be approved by the Emory University Institutional Review Board and registered at clinicaltrials.gov prior to 
enrollment of the first participant.  
Inclusion criteria will be a diagnosis of narcolepsy type 2 or idiopathic hypersomnia.  These diagnoses 
will be made in accordance with the International Classification of Sleep Disorders, third edition (ICSD-3) 
criteria (24).  All participants will have daily sleepiness for at least three months and an absence of cataplexy.  
For patients in whom hypocretin has been tested, values will be above 110 pg/mL.  Participants with narcolepsy 
type 2 will additionally demonstrate a multiple sleep latency test mean sleep latency (MSLT-SL) less than or 
equal to 10 minutes, with at least two sleep onset REM periods (SOREMs) between nocturnal polysomnogram 
and next-day MSLT.  Participants with idiopathic hypersomnia will demonstrate at least one of: 1) MSLT-SL 
less than or equal to 10 minutes, with fewer than two sleep onset REM periods (SOREMs) between nocturnal 
polysomnogram and next-day MSLT; 2) total sleep time of > 660 minutes accrued over up to 24 hours of 
continuous polysomnographic monitoring; or 3) 24-hour total sleep time of > 660 minutes, as estimated by wrist 
actigraphy averaged over at least 7 days.      
Participants suspected of having a diagnosis of narcolepsy type 2 or idiopathic hypersomnia who have 
never had a nocturnal polysomnogram and next-day MSLT, will be scheduled for an additional study visit to 
complete an overnight and day study prior to visit 2.   
Participants already diagnosed with narcolepsy type 2 or idiopathic hypersomnia must be free of wake-
promoting medication or willing to discontinue current wake-promoting medication. Medicines will be 
discontinued for up to two weeks; length of discontinuation will be dependent on the half-life of the 
medication(s).
During the research slow-down created by the COVID19 pandemic, several modifications will be made 
to allow continued data collection while protecting the health of participants, study staff, and the population:
1) Consent and questionnaires will be completed virtually, rather than in-person. The video platform 
that will be used to complete virtual consents and questionnaires is Zoom. This platform is currently 
approved by Emory.

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2) Investigational drug will be shipped directly to the participant from IDS, rather than having the 
participant pick up in person from IDS
3) Inclusion criteria will be changed to eliminate the need for PSG/MSLT.  The Emory sleep lab is 
currently closed for non-urgent procedures, and so no patients suspected of having idiopathic 
hypersomnia or narcolepsy can currently undergo PSG/MSLT.  We will use the following for the 
provisional diagnosis of idiopathic hypersomnia or narcolepsy type 2 during the period that the sleep 
lab is closed for testing:
a.
Clinical suspicion of idiopathic hypersomnia or narcolepsy type 2 by a sleep medicine 
provider
b. Home sleep apnea test demonstrating absence of obstructive sleep apnea (pAHI < 15), if 
sleep medicine provider feels that a home sleep apnea test is clinically indicated to rule out 
sleep apnea
c.
Sleep diary x 1 week demonstrating average sleep time > 7 hours/night and no individual 
nights of < 6 hours
d. Other inclusion/exclusion criteria will continue to apply
Exclusion criteria will include obstructive sleep apnea (AHI > 15), severe periodic limb movements of 
sleep with arousals (PLM arousal index > 30), allergy to either of the study drugs, and contraindication to either 
of the study drugs.  For modafinil, these contraindications include: history of left ventricular hypertrophy, mitral 
valve prolapse, severe cardiovascular disease, unstable angina, myocardial infarction, severe hepatic 
impairment, substance abuse history, psychosis, or unstable depression or mania (25).  Contraindications to 
amphetamine salts, in addition to those listed above, include: other cardiac structural abnormalities, 
cardiomyopathy, severe arrhythmias, uncontrolled hypertension, glaucoma, Tourette’s syndrome, and epilepsy.   
Women who are pregnant, planning to become pregnant within 16 weeks, or breastfeeding will be excluded, as 
the safety of these medications during pregnancy and breastfeeding is not well-established.  Participants who 
have taken either modafinil or amphetamine salts for another indication (e.g., ADHD) will be excluded if it has 
been < 12 months since this treatment.  
Participants who are taking a medication that has a potential interaction with modafinil to cause QTc 
prolongation will be eligible if either: 1) they can safely discontinue the potentially interacting medication prior 
to and throughout the study (in conversation with the prescribing physician), or 2) they undergo an an 
electrocardiogram (EKG) prior to baseline visits that shows a normal QTc interval while on the potentially 
interacting medication.
Patients whose hypersomnia is judged to be due to or primarily associated with a medical or psychiatric 
disease, e.g., Parkinson’s disease, myotonic dystrophy, severe depression, will be excluded.  However, patients 
with a diagnosis of narcolepsy type 2 or idiopathic hypersomnia who have medical or psychiatric comorbidities 
not thought to be causal to daytime sleepiness will not be excluded.  Drs. Trotti and Rye, board-certified 
neurologists, will assess for the relationship between any medical comorbidities and hypersomnolence.  Dr. 
Bliwise, a clinical psychologist, will assess for the relationship between any psychiatric comorbidities and 
hypersomnolence.  
1) The primary outcome will be change in sleepiness from baseline, as measured by the Epworth 
Sleepiness Scale at baseline and week 12.  Secondary outcomes will be sleep inertia and cognitive 
dysfunction.  Current literature does not support the use of a particular, validated instrument for either of 
these measures, which have historically not been assessed in RCTs performed in participants with the 
central disorders of hypersomnolence.  However, stakeholders have identified these two clinical features 
as particularly problematic, and therefore it is important to include measures of change of these 
symptoms in pragmatic clinical trials.  The patient global impression of change (PGI-C) is a validated 
tool to assess change in symptoms (26), which has been used for the assessment of a wide variety of 

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sleep and non-sleep symptoms in clinical trials (27-31).  We will assess three separate PGI-C features: 
sleepiness, sleep inertia (defined for participants as “difficulty waking up and getting out of bed in the 
morning because of sleepiness”), and cognitive dysfunction (defined for participants as “difficulty with 
thinking, problems with attention or concentration, and/or ‘brain fog’”).  For participants taken off meds, 
they will be asked to “compared to the medication (or medications) you were taking just before your 
started the study, which treatment did you prefer overall”. Measures will be collected at baseline, week 
4, week 8, and week 12.  Week 4 and 8 measures will be collected remotely from patients using the 
electronic, HIPAA-compliant REDCap data collection system (32).  Baseline and week 12 measures 
will be collected in a face-to-face visit, mimicking the frequency of follow up in routine clinical 
practice.
Medications will be provided initially as: modafinil 100 mg qam and amphetamine salts 10 mg qam.  
For patients reporting difficulty awakening at baseline, the first dose will be taken 1 hour before planned 
awakening, whenever possible.  For patients without difficulty awakening at baseline, first dose will be taken 
upon awakening.  Patients will be advised to increase dosage once a week with the following schedule: week 2, 
1 pill qam and 1 qnoon; week 3: 2 pills qam and 1 qnoon; week 4 and beyond: 2 pills qam and 2 pills qnoon.  
Patients will be instructed not to titrate further once they feel symptoms are well-controlled and to reduce 
dosage one step in the case of mild to moderate side effects.  In the case of severe side effects, participants will 
be instructed to discontinue treatment but will still continue all remaining study visits and questionnaires.  This 
titration will allow participants to reach doses of modafinil as high as 200 mg bid, the maximum FDA approved 
dose of modafinil in the treatment of narcolepsy.  Participants will reach a maximum dose of amphetamine salts 
of 20 mg bid.  Although the maximum FDA approved dose of amphetamine salts for treatment of narcolepsy is 
higher at 60 mg/day, adverse events are dose-related and higher doses do not necessarily convey additional 
benefit (33); in clinical practice, finding the lowest effective amphetamine dosage and maintaining this dosage 
as long as it is effective is a practical component of the management of both the risk of side effects and the 
problem of tolerance that occurs in 1/3rd patient with narcolepsy treated with amphetamines (34).  
Participants will be randomized to receive a 12-week treatment course with either modafinil or 
amphetamine-dextroamphetamine.  Both are US FDA approved for the treatment of narcolepsy, although are 
considered off-label use for idiopathic hypersomnia.  The main risks of participation are from the study 
medications (which are the standard of care).  Common adverse events include: headache, nervousness, anxiety, 
insomnia, anorexia, xerostomia, palpitations/tachycardia, emotional lability, agitation.  Less commonly reported 
adverse events included: nausea/vomiting, rhinitis, diarrhea, dizziness, dyspepsia, pharyngitis, HTN, chest pain, 
vasodilation, elevated ALT or AST, paresthesia, depression, constipation, abdominal pain, weight loss, 
motor/phonic tic exacerbation, dyspnea, diaphoresis, dysmenorrhea, impotence, visual disturbance, restlessness, 
tooth disorder, photosensitivity.  Rare but serious AEs include:
 
•
dependency, abuse
•
psychosis
•
mania
•
aggressive behavior
•
sudden death
•
myocardial infarction
•
stroke
•
HTN
•
cardiomyopathy (long-term use)
•
seizures
•
hypersensitive reaction, multi organ
•
anaphylaxis
•
Stevens-Johnson syndrome

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•
toxic epidermal necrolysis
•
priapism
•
peripheral vasculopathy
•
Raynaud phenomenon 
•
Growth suppression (long-term use, peds pts)
•
rhabdomyolysis
•
withdrawal signs and symptoms if abrupt discontinuation (prolonged with high dose use)
•
angioedema
•
drug reaction with eosinophilia and systematic signs and symptoms
•
hallucinations
•
suicidal ideation
However, the medications being used in this study are currently standard of care for narcolepsy, being 
tested in this study for equivalency.  Therefore, although there are risks to participation in this research, they are 
of the same magnitude of the risks patients take when seeking treatment for these disorders outside of this 
research.  The benefit to be gained is a clearer understanding of the relative risks and benefits of these 
medications and the clinical features that can help predict response to treatment.  
Community Participation
Dr. Trotti consulted with leadership from the Hypersomnia Foundation and Narcolepsy Network in the 
initial submission of this work and will present results from the study at at least one meeting of one or both of 
these patient organizations following its completion.  
Participant Selection
This study will recruit up to 55 participants, with a sample size target of 44 participants who complete 
participation in the 12 week medication trial.  Participants will be newly diagnosed, medication-naïve 
individuals, or formerly diagnosed, free of wake-promoting medication or willing to discontinue current wake-
promoting medication with diagnoses of: narcolepsy type 2 or idiopathic hypersomnia.  
Inclusion criteria will be: 1) narcolepsy type 2 or idiopathic hypersomnia; 2) age 18-65; 3) informed 
consent.
Exclusion criteria will be: 1) contraindication to modafinil or amphetamine salts (history of left 
ventricular hypertrophy, mitral valve prolapse, other cardiac structural abnormalities, severe cardiovascular 
disease, unstable angina, myocardial infarction, cardiomyopathy, severe arrhythmias, uncontrolled 
hypertension, severe hepatic impairment, substance abuse history, psychosis, glaucoma, Tourette’s syndrome, 
and epilepsy); 2) obstructive sleep apnea (AHI > 15); 3) severe periodic limb movements of sleep with arousals 
(PLM arousal index > 30); 4) allergy to either of the study drugs; and 4) pregnancy or breastfeeding.
Participants who withdraw from study medication will be invited to complete remaining 
questionnaires/study visits.  
Visit Schedule
Visit 1: Enrollment: After reviewing information about the study and confirming participation, subjects will 
answer questions about their sleep disorder and the symptoms experienced.  This visit is expected to last about 
one hour. If participants are suspected of having a diagnosis of narcolepsy type 2 or idiopathic hypersomnia and 
have never had an overnight polysomnogram (PSG) and next-day MSLT, they will be scheduled for an 

8
additional study visit to complete a PSG and MSLT before visit 3. If participants already have a confirmed 
diagnosis of narcolepsy type 2 or idiopathic hypersomnia and are taking certain stimulant medications they will 
be asked to wean off of this medication before and during the study. After weaning off of medicines, the 
participant will be given a four-week supply of one of the two study medications.  The medication will be 
provided will be assigned randomly, the participant and the doctor will not be told which of the two study 
medications are given.  
Visit 2: Participants will only participate in this visit if they haven’t had a sleep study prior to enrollment. 
Sleep testing:  During this visit, participants will come to the Sleep Center for an overnight sleep study, during 
which they will be monitored with multiple wires on their body to measure sleep, breathing, and activity at 
night.  The next day, they will remain at the Sleep Center until approximately 5 pm, taking naps five times 
during the day.  
After these results are received and if the results are positive for a diagnosis of narcolepsy type 2 or idiopathic 
hypersomnia, participants will be given a four-week supply of one of the two study medications and will 
proceed with the remaining study visits. If the results are negative for narcolepsy type 2 or idiopathic 
hypersomnia, participants will be withdrawn from the study.
Visit 3 (four weeks medication dispensed at either Visit 1 or Visit 2): Complete questionnaires and pick up 
medication for the next four weeks (the same medication they have been taking already) at the Emory Sleep 
Center. 
Visit 4 (four weeks after Visit 3):  Complete questionnaires and pick up medication for the next four weeks (the 
same medication they have been taking already) at the Emory Sleep Center. 
Visit 5 (four weeks after Visit 4): Meet with a study team member to discuss experience with the medication.  
Complete questionnaires and return any unused study drug.  

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APPENDIX 1.  SCHEDULE OF STUDY VISITS
VISIT 1
VISIT 2 – 
SLEEP 
STUDY
VISIT 3
VISIT 4
VISIT 5
Informed Consent
X
Medical History
X
Study Inclusion/Exclusion
X
Concomitant Medication Review
X
X
X
X
X
Wean off current wake-
promoting medicines
X
Adverse Experiences
X
X
X
X
Participant Payment
X
X
PSG/MSLT sleep study
X
Sleepy Packet
X
Sleep Inertia Questionnaire
X
X
X
X
X
Epworth Severity Scale 
X
X
X
X
X
CGI- Baseline Questionnaire
X
X
X
X
X
CGI- Sleep Inertia Questionnaire
X
X
X
X
X
CGI- Sleepiness Questionnaire
X
X
X
X
X
CGI- Cognitive Dysfunction 
Questionnaire
X
X
X
X
X
Treatment Questionnaire
X
-
X
X
X
Treatment Comparison 
Questionnaire
X
-
X
X
X
Study Drug Titration Reviewed
X
Randomization
X
OR X
Dispensing or Administration of 
Study Drug
X
OR X
X
X
Counting of Returned Study Drug
X
X
X
Informed Consent Process
Consent will be obtained in-person from a study PI, co-I, or coordinator.  Comprehension will be 
ensured by allowing ample time for questions and discussion and verbally reviewing the information with the 
subject in addition to reviewing the written consent form.  The discussion will take place at the Emory Sleep 
Center.  
Compensation
Participants will be compensated $25 for visit 1 (enrollment) and $25.00 for the week 12 study visit 
(visit 5), for a total of $50.
Statistical Analysis
Sample size will be 22 in each group.  This sample size is sufficient to demonstrate a reduction in ESS 
of 4 points with amphetamine salts, assuming a standard deviation of change from baseline of 6.2 (35).  This is 

10
a conservative, but clinically significant, change in Epworth, compared to the observed change from baseline of 
5.3 points in clinical trials of modafinil [weighted average from (15, 35, 36)].  This sample size provides 82.8% 
power to find a moderately large effect size for amphetamine salts.  For non-inferiority, we will use a responder 
definition of those achieving a 25% reduction in ESS, a data-driven minimal clinically significant change in 
patients with narcolepsy (29).  Assuming 80% of participants meet this threshold, 22 participants per group will 
provide 80% power to a non-inferiority limit of 30% (37, 38).  
Intention-to-treat analyses will be performed, using last observation carried forward in the event of 
participant drop-out.  The change in ESS at week 12 from baseline will be compared between the two treatment 
groups via t-test (compared for unequal variances if necessary) and will be evaluated on a hypothesis of non-
inferiority.  Similar analyses will be performed on secondary outcomes, considering the proportion of 
responders in each treatment arm who rate themselves “much improved” or “very much improved”.  
Categorical outcomes, including these PGI-C proportions and adverse events, will be compared using Chi-
square or Fisher exact test.  Exploratory analyses will evaluate response at week 4 and week 8 between the two 
medications groups, to determine if there is a difference in time to symptom control.  
Considering each medication separately, predictors of response will be assessed using logistic 
regression.  The main predictor of interest will be hypersomnia diagnosis, i.e., narcolepsy type 2 or idiopathic 
hypersomnia.  Other predictors, to be considered in separate, exploratory regression models, include: MSLT 
mean sleep latency, MSLT number of SOREMs, sex/gender, baseline ESS, age, and comorbidities.  Significant 
predictors in univariate models will be combined in a multivariate model.  Although the investigative team has 
extensive clinical trial and statistical experience, additional statistical consultation will be provided as needed 
through Emory’s CTSA consultation program.  
Data Safety Monitoring and Reporting
Participants will be screened for medication contraindications (detailed above) prior to participation, to 
minimize risk of serious drug adverse reactions.  During the study, participants will be encouraged to report any 
adverse events and will be provided with 24-hour contact information with which to do so.  Participants will be 
systematically assessed for expected and idiosyncratic adverse reactions every four weeks during participation.  
Dr. Trotti will review routine adverse event logs at least once a week.  For adverse events reported between 
routine assessments, Dr. Trotti or Dr. Rye will review immediately and provide guidance to the participant on if 
and how to adjust study mediation (e.g., discontinue in the case of a severe adverse reaction) and any additional 
care that should be sought (e.g., urgent or emergency care).  Dr. Trotti will convey any reportable events to the 
Emory IRB using the standard reporting timeline, based on event severity.  Dr. Trotti will also oversee protocol 
compliance and data accuracy.  She will perform reviews of case report forms every four weeks, to ensure 
consistency with protocol and data entry accuracy.  Dr. Trotti and the study coordinator will work together to 
complete the Emory IRB’s “EU Self-Monitoring Tool” (available at 
http://www.ctac.emory.edu/clinical_trial_guidebook/data_and_safety_monitoring_plans.html) every six 
months.  
 
Confidentiality
Data collection will be performed using the REDCap research tool, including online assessments.  
REDcap provides secure, web-based applications that offer easy data manipulation with audit trails for 
reporting, monitoring, and querying patient records and an export mechanism to statistical programs (e.g., 
SAS).  REDcap servers are housed in a local data center at Emory University and all web-based information 
transmission is encrypted.  REDcap was developed specifically to be compliant with HIPAA-security 
guidelines.  Paper records (e.g., consent forms) will be stored in a locked office.  When subsets of data are 

11
housed on individual computers for data analysis and manuscript preparation, the minimum amount of 
identifiers will be included and computers will be encrypted.  
Citations
1.
Morgenthaler TI, Kapur VK, Brown T, Swick TJ, Alessi C, Aurora RN, et al. Practice parameters for the 
treatment of narcolepsy and other hypersomnias of central origin. Sleep. 2007;30(12):1705-11.
2.
Khan Z, Trotti LM. Central Disorders of Hypersomnolence: Focus on the Narcolepsies and Idiopathic 
Hypersomnia. Chest. 2015;148(1):262-73.
3.
Black J, Swick T, Bogan R, Lai C, Carter LP. Impact of sodium oxybate, modafinil, and combination 
treatment on excessive daytime sleepiness in patients who have narcolepsy with or without cataplexy. Sleep 
Med. 2016;24:57-62.
4.
Sonka K, Susta M, M. B. Narcolepsy with and without cataplexy, idiopathc hypersomnia with and 
without long sleep time: a cluster analysis. Sleep Medicine. 2015;epub ahead of print.
5.
Trotti LM, Staab BA, Rye DB. Test-retest reliability of the multiple sleep latency test in narcolepsy 
without cataplexy and idiopathic hypersomnia. J Clin Sleep Med. 2013;9(8):789-95.
6.
Ruoff C, Pizza F, Trotti LM, Sonka K, Vandi S, Cheung J, et al. The MSLT is Repeatable in Narcolepsy 
Type 1 But Not Narcolepsy Type 2: A Retrospective Patient Study. J Clin Sleep Med. 2017.
7.
Lopez R, Doukkali A, Barateau L, Evangelista E, Chenini S, Jaussent I, et al. Test-Retest Reliability of 
the Multiple Sleep Latency Test in Central Disorders of Hypersomnolence. Sleep. 2017;40(12).
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