Conditions: Insomnia Insomnia Chronic
Keywords: insomnia sleep chronic insomnia zolpidem ambien
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 197
Healthy volunteers: no

Brief summary:
The study is a three phase sequential study of the medical treatment of insomnia with zolpidem. All participating subjects will receive one month of standard nightly treatment. If the subject has a positive treatment response they continue in the study and are randomized to one of four conditions: intermittent dosing (3-5 pills week, full dose), or one of three variable dose conditions (nightly pill use where any given pill is a variable dose). Standard treatment will last for 4 weeks. The experimental phase will extend over two periods. The first period will last for 12 weeks. The second period will last for 36 weeks. Both periods include:

• Taking a pill 30 minutes prior to bedtime.

In one case, this will involve taking 3-5 pills per week. In the remaining condition pills will be taken on each and every night. Depending on the specific group that the subject is assigned to, they will either receive 10mg or 5mg of zolpidem (variable by age and sex) or a variable dose of zolpidem on a nightly basis (range from 0 mg to 10 mg per night).

* Completing a sleep diary each day;
* Completing 6 to 7 questionnaires each week;
* A monthly visit to Penn to return your medication foil packs and to receive a new foil pack with the next month of medication.

During Phases 3\&4, the subject will be asked to undergo quarter annual physicals so that we can optimally track their health and wellbeing. The physicals will involve standard vitals measures (e.g., temperature, blood pressure, height and weight, etc.) and, based on the judgement of the research clinician, may involve an EKG and blood and urine chemistries.

If the subject does not experience a treatment response or (following a treatment response) experiences a relapse of insomnia, they will not continue in the study but will be given the opportunity to be treated with Cognitive Behavioral Therapy for Insomnia (CBT-I) at no cost. Assessments of the subjects clinical status will be based on your daily sleep diaries and weekly questionnaires.

Detailed description:
Phase-1: Initial Evaluation.

This evaluation occurs at the offices of the Behavioral Sleep Medicine Program (Suite 670, 3535 Market Street Philadelphia, PA 19104) and lasts about 1 to 2 hours. Procedures include:

* Completing forms asking questions about your sleep, mood, alcohol use, medical history, your current medications, and background questions about your age, race, and education.
* The provision of your consent to contact your primary care provider to gain their assent (agreement) that you may participate in the trial safely.

The information obtained during the initial assessment will be used to see if you are eligible to participate in this study. If you are determined ineligible, you will not be able to continue in the study but will be provided with a referral if appropriate.

NOTE: This study will be using an Internet Data Portal (IDP) system to collect most questionnaire data. The IDP is a Research Electronic Data Capture and is a secure web application. It is a password protected site located on Penn's servers in which the data will live in a database online where only qualified research personnel can access it. During the initial evaluation you will be introduced to this system and provided with a username and password. The study staff will assist you in filling out the questionnaires using this IDP system.

Phase-2: Baseline Period.

This phase lasts 14 days. Your participation includes:

* Completing daily sleep diaries at home. The online diary form requires about 5 minutes each day to complete.
* Completing 6 to 7 forms asking questions about your medical symptoms, and sleep each week of the baseline period. These online questionnaires require about 15 minutes to complete.
* Abstaining from the use of any medication or over the counter product that is used expressly for the purpose of helping you fall or stay asleep (e.g. trazadone/Desyrel, melatonin, Nyquil, Tylenol PM, Benadryl, etc.). If you choose to discontinue your current sleep medication to participate in our study, please do this in consultation with the clinician that prescribed your sleep medication. Please note that discontinuation of your current sleep medication will make it necessary to extend the baseline component of our study by at least two weeks. Should the sleep diaries indicate that your insomnia is not of the type, severity, or frequency required for the study, you will not be able to continue in the study but will be provided with a referral. This referral will be for the Penn Sleep Disorder Center. If you or study personnel deem your two weeks to be unusual, you may be offered the chance to repeat the baseline period.

Phase-3: Sleep Lab Study (polysomnography) or Home Sleep Apnea Test (HSAT). You will undergo a polysomnography study or an HSAT to determine if you are eligible to continue in the study. During the pandemic all sleep tests will be administered at home. After the pandemic, the study investigators will decide which type of study you will receive. Both sleep assessments will last for 1 night.

The HSAT equipment will be shipped to your house. A member of the study team will contact you to go over proper use instructions. On the night of the test, you can go to bed at your regular bedtime. Prior to bedtime, you will attach the sensor(s) as instructed and start the test. Upon waking up, you will stop the test and remove the sensor(s). On the day immediately following the sleep test, you will ship the device back in the prepaid shipping envelope Procedures for the polysomnography study are: you will be asked to arrive at the sleep lab located at the Hospital of the University of Pennsylvania (HUP) at the cross streets of 34th and Spruce by 7 P.M. for a polysomnographic study (PSG). Upon arrival, to ensure for accurate laboratory measurements, urine toxicology screens may be performed to rule out illegal substance use. These data are acquired to explain abnormal findings on the PSG. Following the sleep study, it will be determined whether a repeat study is necessary based on the findings both from the clinical chemistries and the polysomnography. If a repeat study is necessary, one of the project investigators will discuss the issue of substance use with you to: (1) determine if the clinical chemistries' finding was an error (for example poppy seeds led to a positive screen) or (2) gain your willingness to refrain from substance use for the second PSG and for the remainder of the study. If you screen positive a second time, your participation will be discontinued.

The specific procedure for a PSG requires that you have a set of sensors placed on your face, scalp, and body by a technician. All the sensors are attached with surgical tape, paste and glue. The sensors on your face are attached on your left and right temple, cheek bone and under your nose. The sensors on the temple and cheek bone measure eye movements associated with falling asleep and dreaming. The sensors under your nose measure airflow through your mouth and nose. The sensors on your scalp measure brain waves during sleep. The sensors on the body are placed above the collar bones and over the calf muscles. The sensors over the collar bones measure heart muscle activity. The sensors over the calf muscles measure muscle activity from the legs. In addition, a strap will be placed around your chest and abdomen to measure respiration.

After you have been connected to the equipment, you are expected to stay in bed until final wake time the next morning, except for bathroom breaks. You will be visually monitored by the lab technicians by remote video. In the morning, you will be awakened by the technician (if needed), be unhooked from the equipment, and then allowed to shower, dress, and eat before leaving. You will be free to go about your normal schedule for the rest of the day.

If the in-lab PSG sleep or HSAT study finds evidence of a sleep disorder other than insomnia, such as sleep apnea, you will not be able to continue in the study but will be provided with a referral.

Phase-4: Standard Treatment. All participating subjects will receive one month of standard nightly treatment. If you have a positive treatment response you will remain in the study and be randomized to one of the following treatment conditions: nightly dosing, intermittent dosing (1-3 pills week, full dose), or one of two variable dose conditions (nightly pill use where any given pill is a variable dose). The assignment of condition will be accomplished by a process that is the same as the flip of a coin and neither you nor the study personnel will know which condition you have been assigned to (this is referred to as a "double blind" study). You will have an equal chance of being randomized to each of the 4 study arms. In the case of an emergency, the blind will be broken and the study doctor and clinicians associated with your care will be informed of which dosing condition you were assigned to.

Standard treatment will last for 4 weeks. The experimental phase will extend over two periods. The first period will last for 12 weeks. The second period will last for 36 weeks.

Both periods include:

* Taking a pill 30 minutes prior to bedtime. In one case, this will involve taking 1-3 pills per week. In the remaining conditions, pills will be taken on each and every night. Depending on the specific group you are assigned to, you will either receive 10mg or 5mg of zolpidem (variable by age and sex) or a variable dose of zolpidem on a nightly basis (range from 0 mg to 10 mg per night). Please note that the effect of zolpidem may be slowed if taken with or immediately after a meal.
* Completing a sleep diary each day;
* Completing 6 to 7 questionnaires each week;
* A monthly visit to Penn to return your medication foil packs and to receive a new foil pack with the next month of medication.

If you do not experience a treatment response or (following a treatment response) you experience a relapse of insomnia, you will not be able to continue in the study but will be given the opportunity to be treated with Cognitive Behavioral Therapy for Insomnia (CBT-I) at no cost. Assessments of your clinical status (how your insomnia is responding to treatment) will be based on your daily sleep diaries and weekly questionnaires.

During Phase-4, you will be asked to undergo quarter annual physicals so that we can optimally track your health and wellbeing. The physicals will involve standard vital measures (e.g., temperature, blood pressure, height and weight, etc.) and, based on the judgement of the research clinician, may involve an EKG and/or blood and urine chemistries.

Arms:
arm 1: Nightly active dose (QHS). The intervention is zolpidem tartrate 5 mg or 10 mg. arm 2: 1 active dose per week with 6 placebos interspersed between the active dose. The intervention is zolpidem tartrate 5 mg or 10 mg. arm 3: 3 active doses per week with 4 placebos interspersed between the active doses. The intervention is zolpidem tartrate 5 mg or 10 mg. arm 4: 1 to 3 active doses per week, on night chosen by participant (as needed). The intervention is zolpidem tartrate 5 mg or 10 mg.

Interventions: intervention 1: Zolpidem tartrate
Intervention descriptions: intervention 1: Zolpidem Tartrate, 5mg for men older than 60 and women of all ages. 10 mg for men younger than 60.

Protocol document:
Prot_SAP_005.pdf: 
Official Study Title: Three Approaches to Maintenance Therapy for 
Chronic Insomnia in Older Adults 
NCT Number: NCT03774810
Date: 04/12/2022
Cover Page


Axsome/Solriamfetol 
 
Page 1 
 
The Effects of Solriamfetol and CBT-I (alone and in combination) on Sleep Continuity, Sleepiness, Fatigue, and 
Performance in Patients with Insomnia Disorder. 
 
Principal Investigator 
Michael Perlis 
Department of Psychiatry 
Suite 670, 3535 Market Street 
215-746-3577 or 585-737-2531 
mperlis@upenn.edu 
 
Regulatory Sponsor  
 
This work is supported by Axsome Pharmaceuticals 
NIH Grant Number 
N/A 
Investigational Product: 
Solriamfetol 
Protocol Number: 
850945 
IND/ IDE Number: 
[If applicable] 
N/A 
ClinicalTrials.gov Number 
In process 
Title 
The Effects of Solriamfetol and CBT-I (alone and in combination) 
on Sleep Continuity, Sleepiness, Fatigue, and Performance in 
Patients with Insomnia Disorder. 
Short Title 
Solriamfetol and CBT-I 
Study Summary 
Medication is FDA approved. The objective of this project is to 
test the efficacy of solriamfetol for treating insomnia (alone and 
in combination with CBT-I). Ultimately, this study will test 
whether wake extension (regardless of how it is achieved) will 
consolidate sleep and improve sleep continuity. 
Methodology 
Please see investigational plan for more information 
Study Duration 
12-18 months 
Study Center(s)  
One site only: Penn Behavioral Sleep Medicine Program 
Objectives 
1. To investigate the effects of solriamfetol on sleep continuity, 
alone and in combination with CBT-I. 
2. Assess the effects of solriamfetol on daytime sleepiness, 
fatigue, adherence with “sleep rescheduling”, and on daytime 
performance 
Number of Subjects 
We will enroll and complete 40 subjects with Insomnia Disorder 
(60 recruited and a min. of 40 completed subjects). 


Main Inclusion and 
Exclusion Criteria  
Subjects. Subjects will be between the ages of 25-65 years old 
and have a stable sleep/wake schedule (no shift work) with a 
preferred sleep phase between 9:00 PM and 9:00 AM. 
 
Inclusion Criteria. Adults > 25 and < 65 years of age with chronic 
insomnia who meet DSM-5 criteria for Insomnia Disorder and 
ICSD-3 criteria for Psychophysiologic insomnia. In addition, all 
subjects will have a sleep initiation and/or a sleep maintenance 
complaint (> 30 min. to fall asleep and/or > 30 min. of 
wakefulness during the night) with a problem frequency > 3 
nights/wk and problem duration > 3 mo. This profile must be 
evident at both intake (based on retrospective reports) and as 
an average profile from the two weeks of baseline diaries (based 
on prospective sampling). 
 
Exclusion Criteria for All Subjects. In brief, the exclusionary 
criteria are currently in treatment for insomnia, unstable 
medical or psychiatric illness, night shift work, and/or a history 
of other sleep disorders. 
 
Investigational Product 
(drug, biologic, device, 
etc.) 
 
Solriamfetol (trade name: Sunosi), 75mg. 
Duration of 
administration  
(if applicable) 
4 weeks 
 
Reference therapy 
 
 Cognitive Behavioral Therapy for Insomnia (CBT-I) 
Statistical Methodology 
A 2x2 mixed model design. The two factors will be 1) treatment 
(+/- solriamfetol and +/- CBT-I) and 2) Time (pre-post 
assessment, with additional follow-up data). 
Safety Evaluations  
Daily diary assessments of side effects, weekly symptom 
checklists to monitor the health status of subjects (upon 
disbursement of medication). We will utilize a side-effect check 
list based on the package insert for Solriamfetol. 
Data and Safety 
Monitoring Plan  
We will establish a four-person advisory board comprised of a 
second MD sleep medicine specialist, a clinical psychologist, a 
nurse sleep scientist, and a biostatistician. Membership consists 
of persons completely independent of the investigators who 
have no financial, scientific, or other conflicts of interest with 
the trial. Collaborators of the PIs will not be eligible to serve on 
the advisory board. The board will receive reports from the 
study team every six months with information about the 
progress of recruitment, the demographic characteristics of 
participants, serious adverse events, the number of dropouts, 
and participants’ reasons for dropping out, and any protocol 
amendments. These meetings will focus on the conduct and 
progress of the study, including participant accrual, protocol 
compliance, and problems encountered. 


 
 
 
 
 
BACKGROUND AND STUDY RATIONALE 
 
1. Introduction 
 
        Background and Relevant Literature  
Presently, treatment for insomnia (in the case of cognitive behavioral treatment for insomnia [CBT-I]) focuses on 
limiting time in bed to reduce night-time wakefulness, thereby improving sleep continuity and daytime performance. 
The proposed project approaches insomnia treatment differently: the same outcomes may be achieved by enhancing 
and/or extending wakefulness during the day. The current proposal will test whether enhancing daytime wakefulness 
using a wake-promoting medication, solriamfetol, can improve sleep continuity and daytime performance, both as a 
stand-alone and in combination with CBT-I. 
 
The current pharmacological approach for the treatment of insomnia is largely sedative medications, which promote 
sleep and have some benefit, but considerably limited efficacy compared to cognitive behavioral treatment for 
insomnia (CBT-I). Part of the mechanism of action for CBT-I is that over the course of 2-6 weeks of behavioral 
treatment, time in bed is severely limited, which has the intended outcome of increasing homeostatic sleep drive and 
thereby reducing night-time wakefulness. The current unknown is whether implementing this mechanism via wake-
promoting medication can achieve efficacious outcomes. It is expected (given a common mechanism [wake 
extension]) that both CBT-I and treatment with solriamfetol [SFTRL] will improve sleep continuity, and that such 
effects will potentially be additive. Preliminary work by our group with another wake promoting medication suggests 
that such outcomes are feasible (PMID: 15283007). If successful, this unique treatment approach may provide an 
important alternative for patients that do not tolerate sleep restriction during CBT-I or for whom the transient 
iatrogenic sleepiness of CBT-I represents an unacceptable risk (e.g., surgeons, pilots, etc.). 
 
2. Name and Description of the Investigational Product  
 
Solriamfetol (trade name Sunosi), is a norepinephrine-dopamine reuptake inhibitor available in 75mg and 150mg tablets 
for oral administration during the day. Solriamfetol’s primary indication is to treat excessive daytime sleepiness (EDS) in 
patients diagnosed with OSA or Narcolepsy. It binds to the dopamine transporter and the norepinephrine transporter with 
affinities (Ki) of 14.2 μM and 3.7 μM, respectively), does not undergo significant metabolism in humans, and has a Tmax 
of ~2 hours (range 1.25–3.0 hours) and a T1/2 of ~7.1 hours. The pharmacokinetic profile of solriamfetol, along with the 
absence of active metabolites, makes it unlikely that there are accumulation effects with multiple doses over days. See 
the attachment for a copy of the package insert for solriamfetol.  
 
Solriamfetol will be provided by Axsome Pharmaceuticals (no cost), and managed by, the Investigational Drug Services of 
the University of Pennsylvania. An over encapsulation technique will be used to ensure that the drug doses and placebo 
formulations appear identical.  The first five participants will be enrolled slowly to observe whether any adverse responses 
occur (e.g., taking longer to fall asleep after medication administration at 2pm) that would necessitate protocol 
modifications, for instance to the timing of medication dosing, if not amount. 
 
Solriamfetol or placebo will be administered at 2pm daily for 4 weeks. Dosage will (for all subjects) start at 75mg. This 
dosage was chosen through weighing up the need to extend wake/delay bedtime to consolidate sleep and improve sleep 
continuity (necessitating a later timing of dose than typical), without inadvertently enhancing wake to the point where it 
extends sleep latency. Rather than downwardly titrate the medication, the timing of dosing will be altered where required 
(for example, timing advanced to 1pm or 12pm). Changes in dose timing will occur when the study staff (therapist, PI, and 
medical collaborator) deem it to be optimal (i.e., in response to extended sleep latency). Subjects in the SRFT + CBT-I arm 
will also be eligible for changes in dose timing if they report being unable to adhere to the prescribed time to bed (PTTB) 
component of CBT-I. As noted above, medication use will also include a 1-week placebo run-in and a 3-week placebo “run-
out” (eight weeks’ total). The timing of the first administration of SRFTL will (for those receiving CBT-I) align with the start 
of sleep restriction (Session 2).  
 
All study medication will be provided by Axsome Pharmaceuticals (no cost) and will be received, stored, and packaged by 
the University of Pennsylvania Investigational Drug Service (IDS). IDS will create blister packs for each patient that are 
identical and will allocate active medication and placebo according to treatment condition. This will enable double blinding 
of the study. All doses will be over-encapsulated, and all daily doses will be delivered as a single capsule. The use of blister 


packs will also allow us to not only track adherence but to identify the patterning of medication use. Blister packs will be 
returned once a month when subjects will be evaluated and provided the next month’s medication supply. The study CRC 
will dispense and receive the foil packs. The pattern of used and unused data will be coded.   
 
2.1 
Nonclinical and Clinical Data To Date 
The use of solriamfetol to treat EDS has been evaluated and extensively profiled in the literature. Given the shared EDS 
phenotype between narcolepsy, OSA, and insomnia, such data support that solriamfetol may be useful in those patients 
who cannot or do not tolerate the iatrogenic effects of sleepiness in CBT-I. Three such studies are listed below:   
 
Krystal, A. D., Benca, R. M., Rosenberg, R., Schweitzer, P. K., Malhotra, A., Babson, K., ... & Strohl, K. P. (2022). 
Solriamfetol treatment of excessive daytime sleepiness in participants with narcolepsy or obstructive sleep apnea 
with a history of depression. Journal of psychiatric research, 155, 202-210. 
 
Subedi, R., Singh, R., Thakur, R. K., Bibek, K. C., Jha, D., & Ray, B. K. (2020). Efficacy and 
safety of solriamfetol for excessive daytime sleepiness in narcolepsy and obstructive sleep 
apnea: a systematic review and meta-analysis of clinical trials. Sleep Medicine, 75, 510-
521. 
 
Servid, S. (2012). New Drug Evaluation: solriamfetol tablets, oral. 
 
2.2 
Human Pharmacokinetics 
The time to peak levels of solriamfetol is about 2 hours (range 1.25–3.0 hours).    
Solriamfetol is minimally metabolized in humans. Its elimination half-life is about 7.1 hours. 
 
2.3 
Clinical Studies in Adults  
Please see section 1.2.1 
 
2.4 
Clinical Studies in Children  
N/A 
 
2.5 
 Dose Rationale (if applicable) 75mg was chosen through weighing up the need to extend wake/delay bedtime to 
consolidate sleep and improve sleep continuity (necessitating a later timing of dose than typical), without inadvertently 
enhancing wake to the point where it extends sleep latency. Rather than downwardly titrate the medication, the timing 
of dosing will be altered where required (for example, timing advanced to 1pm or 12pm). Changes in dose timing will 
occur when the study staff (therapist, PI, and medical collaborator) deem it to be optimal (i.e., in response to extended 
sleep latency). Subjects in the SRFT + CBT-I arm will also be eligible for changes in dose timing if they report being unable 
to adhere to the prescribed time to bed (PTTB) component of CBT-I.  
 
3 
Study Objectives 
As noted above, the current proposal is for a one-year study to investigate whether solriamfetol can improve sleep 
continuity and daytime performance, alone and in combination with CBT-I. It is expected (given a common mechanism 
[wake extension]) that both CBT-I and treatment with solriamfetol will improve sleep continuity, and that such effects will 
potentially be additive. 
 
3.1 
Primary Objective(s)  
To investigate the effects of solriamfetol on sleep continuity, alone and in combination with CBT-I.  
 
3.2 
Secondary Objectives (if applicable) 
Assess the effects of solriamfetol on daytime sleepiness, fatigue, adherence with “sleep rescheduling”, and on daytime 
performance 
 
4. Investigational Plan  
All subjects will be monitored for 2 weeks prior to treatment, for 8 weeks during treatment, and for 2 weeks following 
treatment. Additionally, subjects will complete two questionnaires complete two questionnaires (Insomnia Severity Index 
[ISI] and Retrospective Sleep Continuity Assessment Questionnaire [RSCAQ]) 3 months after completing treatment.3 
months after completing treatment. Subjects receiving solriamfetol will take medication at 2pm daily for 4 weeks. 
Medication use will also include a 1-week placebo run-in and a 3-week placebo “run-out” (8 weeks’ total). Note: This 
design was used for our prior trials of CBT-I with wake promoting medications. Subjects receiving CBT-I will have 8 weekly 


sessions (up to 90 minutes in duration). Daily sleep diaries will be administered to assess for differences in sleep continuity 
between conditions and over time. Self-report weekly assessments will also be administered and will include standard 
retrospective measures of insomnia (ISI), sleepiness (Epworth Sleepiness Scale, ESS), depression (PHQ-9), fatigue 
(Functional Assessment of Chronic Illness Therapy – Fatigue Scale [FACIT-Fatigue], PROMIS-Short Form 7a, and Brief 
Fatigue Inventory [BFI]), treatment acceptability (MITAS)), and daytime function (Functional Outcomes of Sleep-10 item, 
FOSQ-10). Daytime function will also be objectively assessed daily via Ecological Momentary Assessment and at the end 
of baseline treatment, and post treatment periods using a PVT phone-based app. Self-report assessments will be 
accomplished on-line via RedCap software and subjects will also be asked to complete weekly and monthly questionnaires 
via Hypknowledge (a PHT Penn Health Tech Clinical Research Tool) site. 
 
Treatment Regimen (as noted above) 
The first five participants will be enrolled slowly to observe whether any adverse responses occur (e.g., taking longer to 
fall asleep after medication administration at 2pm) that would necessitate protocol modifications, for instance to the 
timing of medication dosing, if not amount. 
Medication: Solriamfetol (SRFTL) or placebo (PLA) will be administered at 2pm daily for 4 weeks. Dosage will (for all 
subjects) start at 75mg. This dosage was chosen through weighing up the need to extend wake/delay bedtime to 
consolidate sleep and improve sleep continuity (necessitating a later timing of dose than typical), without inadvertently 
enhancing wake to the point where it extends sleep latency. Rather than downwardly titrate the medication, the timing 
of dosing will be altered where required (for example, timing advanced to 1pm or 12pm). Changes in dose timing will 
occur when the study staff (therapist, PI, and medical collaborator) deem it to be optimal (i.e., in response to extended 
sleep latency). Subjects in the SRFT + CBT-I arm will also be eligible for changes in dose timing if they report being unable 
to adhere to the prescribed time to bed (PTTB) component of CBT-I. As noted above, medication use will also include a 1-
week placebo run-in and a 3-week placebo “run-out” (eight weeks’ total). The timing of the first administration of SRFTL 
will (for those receiving CBT-I) align with the start of sleep restriction (Session 2).  
All study medication will be provided by Axsome Pharmaceuticals (no cost) and will be received, stored, and packaged by 
the University of Pennsylvania Investigational Drug Service (IDS). DS will create blister packs for each patient that are 
identical and will allocate active medication and placebo according to treatment condition. This will enable double blinding 
of the study. All doses will be over-encapsulated, and all daily doses will be delivered as a single capsule. The use of blister 
packs will also allow us to not only track adherence but to identify the patterning of medication use. 
Cognitive Behavioral Therapy: Treatment will be conducted by a master therapist via a HIPAA compliant video link (Zoom), 
with 1-2 members of our established cohort of CBT-I experts (n=17) serving as backup therapists. Sessions 1-8 will follow 
our published protocol (published in 2005 by Springer). Each session will be conducted individually and have a singular 
focus per session. All sessions following the delivery of sleep restriction therapy & stimulus control instructions (post 
Session 2) will include, as needed, management of non-adherence and/or time-in-bed titration. The Session specific 
itinerary will be as follows.  
Session 1: evaluation and orientation 
Session 2: data acquisition and delivery of sleep restriction therapy & stimulus control instructions 
Session 3: review of sleep hygiene  
Session 4: management of non-adherence and/or time-in-bed titration only 
Session 5: cognitive therapy [de-catastrophization] 
Session 6: management of non-adherence and/or time-in-bed titration only 
Session 7: management of non-adherence and/or time-in-bed titration only 
Session 8: review of treatment progress and relapse prevention.  
All treatment will be delivered by a single master therapist (DA Posner PhD CBSM). Dr. Posner has more than 27 years’ 
experience with CBT-I, he is one of the authors of our published treatment manual (1), and he is also a co-author of a 
second CBT-I treatment manual (2). He was a consultant for the VA’s rollout of CBT-I, he jointly conducts the Penn 3-day 
Basic and Advanced CBT-I courses, and he regularly conducts on-site one-day CBT-I workshops. As a final testament to his 
expertise, he was one of the first individuals to be certified in behavioral sleep medicine and one of the first to receive the 
SBSM’s Distinguished Career Achievement Award. 


 
5. General Design 
A double blind 2x2 mixed model design. The two factors will be 1) treatment (+/- solriamfetol and +/- CBT-I) and 2) Time 
(pre-post assessment, with additional follow-up data). Patients with insomnia will be randomly assigned to treatment 
condition. 
 
5.1 Screening  
Participants with insomnia will be recruited via established recruitment approaches. Advertising includes social media 
strategies, which have been found to be maximally productive (e.g., Google and Facebook Ads where the catchment is 
limited to within 60 miles of Philadelphia). Potential participants will be provided with contact information and a link to 
our screening page (www.sleeplessinphilly.com), which has proved successful in past studies. The study CRC and/or PI will 
review the screening form and contact the participant via e-mail to let them know whether or not they pass this screening 
stage. If so, participants will provide physician assent to confirm eligibility. If they are eligible, the CRC and/or the PI will 
follow-up with the participant via HIPAA compliant telehealth to complete the consent and provide more information 
about the study.  
 
Please note that the intake questionnaires to be used include a set of measures that are validated and a set of measures 
that are specific to our laboratory. Subjects that are still eligible after the intake interview will be instructed to obtain their 
PCP’s assent to participate in the study.   
 
Following the intake, all subjects that remain eligible for the proposed study will complete two more assessments prior to 
being enrolled in the proposed experiment. First, each subject will complete two weeks of daily sleep diaries to confirm 
1) their retrospective estimates regarding the type, severity, and frequency of their insomnia and 2) that they are 
compliant with the daily task of completing the daily diaries. Second, each subject will undergo a Home Sleep Apnea 
Testing (HSAT, type 3 or 4 sleep study) study to rule out the presence of occult sleep disorders (sleep disorders for which 
the patient does not exhibit the typical signs and symptoms). This sleep study will be equivalent to the quality of a clinical 
PSG. These screenings will be conducted according to the Penn CSI Sleep Research Laboratory’s standards. The recording 
montage consists of 14 electrophysiological signals. The basic montage includes 2 EOGs referenced to a single mastoid 
[LOC & ROC], 6 EEGs referenced to linked mastoids [F3, F4,C3,C4,O1,&O2,], 1 bipolar mentalis EMG, an EKG, 2 bipolar 
tibial EMGs, a nasal/oral airflow thermocouple, 2 respiratory effort sensors, and an oximeter measure of blood oxygen 
saturation. All 14 signals will be recorded with SD32 amplifiers and use Sandman v10 acquisition software to transmit data 
directly to the control room where the PSG can be monitored online and simultaneously recorded to PCs located in the 
control room. PSG data will be scored according to Rechtschaffen, and Kale’s standards and the sleep continuity and sleep 
architecture variables will be calculated using lab standard definitions. Additionally, AI/AHI indices will be calculated 
according to AASM criteria. Subjects with an AI (vs. AHI) of >10 will be ineligible for the proposed study. 
 
5.2 Study Intervention Phase  
See section 3.0 – Investigation Plan.  
 
5.3 Phase II (if applicable include and add details about open label study phase if appropriate)  
See section 3.0 – Investigation Plan.  
 
5.4 Follow Up Phase 
Three months after completion of treatment, subjects will complete two questionnaires (Insomnia Severity Index [ISI] and 
Retrospective Sleep Continuity Assessment Questionnaire [RSCAQ]). 
  
5.5 Allocation to Interventional Group  
The study statistician and/or staff member of the Investigational Drug Services will execute the randomization procedures.  
 
5.6  Study Endpoints  
Primary hypothesis 
1. Patients administered solriamfetol will have significantly greater improvements in sleep continuity (total wake time 
[TWT]) from baseline to post-treatment compared to patients administered placebos. Note: the study is powered for 
this hypothesis. 
5.6.1 
Primary Study Endpoints 
As noted in section 3.2 


5.6.2 
Secondary Study Endpoints 
1. Patients treated with CBT-I will have significantly greater improvements in sleep continuity from baseline to post-
treatment compared to patients not administered CBT-I.  
2. Patients treated with CBT-I in combination with solriamfetol with have significantly greater improvements in sleep 
continuity from baseline to post-treatment compared to patients treated with CBT-I alone.  
3. Exploratory hypotheses: Patients treated with CBT-I in combination with solriamfetol will have significantly 
greater adherence with sleep restriction (i.e., sleep rescheduling, prescribed time to bed [PTTB]) and on daytime 
performance measures (e.g., ESS, FSS, etc.) compared to CBT-I alone. 
 
i. Primary Safety Endpoints [if applicable] 
As noted above, side effects will be assessed in several ways: daily assessments via the sleep diaries, weekly evaluation 
with a medical symptom checklist (52 symptoms where positive endorsements allow subjects to rate their average 
severity and number of days affected). 
 
 
6. Study Population and Duration of Participation  
Subjects 25 to 65 years old (inclusive) and who have a stable sleep/wake schedule (no shift work) with a preferred sleep 
phase between 10:00 PM and 8:00 AM. The recruitment sample will be populated by 40 completed subjects. The study 
duration will be 12 weeks, with a one-time follow-up at 3 months post-treatment. 
 
a. Inclusion Criteria 
Participants will meet the diagnostic criteria for Insomnia Disorder according to Diagnostic and Statistical Manual of 
Mental Disorders (DSM–5). The complaint of disturbed sleep will meet the following criteria: 
• 
≥ 30 minutes to fall asleep (SL) and/or ≥ 2 awakenings per night of ≥ 15 minutes duration and/or wake after 
sleep onset (WASO) time of ≥ 30 minutes where total sleep time (TST) did not exceed 6 hours (unless sleep 
efficiency [SE] is ≤ 80%). 
• 
The problem is present for > 3 nights per week. 
• 
The problem duration exceeds ≥ 6 months. 
• 
The complaint of impaired daytime function must include, although not limited to, the report of daytime fatigue, 
sleepiness, or both. 
 
Additional inclusion criteria are as follows.  
1. Aged 25 to 65 years (inclusive).  
2. Have a preferred regular sleep phase between 10:00 PM and 8:00 AM. 
 
b. Exclusion Criteria 
 
Please note that all subjects will have to receive physician assent before being enrolled into the  
study. 
 
Use of medication expressly for the purpose of falling or staying asleep (e.g., trazadone/ desyrel, melatonin, Tylenol 
PM, Nyquil, Benadryl). 
          Assessed with patient Hx 
          While medication can be used while participating in CBT-I, it is recommended that medications taken for sleep be 
discontinued. 
 
Night shift work 
            Assessed with patient Hx 
            To ensure enrolled subjects are on a normal sleep schedule  
 
Compromised renal function 
 
      Assessed with patient Hx 
 
      Will ascertain physician assent 
 
      To ensure the safety of the subject as Solriamfetol has been found to be contraindicated in  
                     those with renal impairment. 
 


      Use of MAOIs 
 
   Assessed with patient Hx 
 
   Will ascertain physician assent 
 
   To ensure safety as MAOIs are contraindicated with the concurrent use of solriamfetol 
 
      Major Coronary Artery Disease and/or uncontrolled (with meds) Hypertension 
 
    Assessed with patient Hx 
 
    Will ascertain physician assent 
 
   To ensure safety as solriamfetol is contraindicated in patients with these disorders 
 
       Planning to become pregnant, pregnant, and/or breastfeeding 
 
   Assessed with patient Hx (will ensure use of birth control methods on the screening form) 
   To ensure safety as solriamfetol has not been demonstrated to be safe for use while pregnant    
   and/or breast feeding. 
 
Unstable medical or psychiatric illness 
Assessed with the patient Hx, PHQ-9, and the GAD-7    
Assessed with a History and Physical, an EKG, and a clinical chemistries panel  
To ensure that the insomnia is not comorbid with unstable medical or psychiatric illness (e.g., Bipolar Disorder) 
 
Symptoms suggestive of sleep disorders other than insomnia  
Assessed with the Sleep Disorders Symptoms Checklist (SDS-CL).  
To ensure that the insomnia is not comorbid with other intrinsic sleep disorders  
 
Polysomnographic data indicating sleep disorders other than insomnia 
Assessed with Home Sleep Apnea Testing (HSAT, type 3 or 4 sleep study).  
Subjects w/ an AI of >10 are excluded from the study 
 
Subjects w/ an abnormal Home Sleep Apnea Testing (HSAT, type 3 or 4 sleep study) are excluded from the study 
To ensure that the insomnia is not comorbid with other intrinsic sleep disorders.  
 
Evidence of active illicit substance use, abuse, or dependence 
Assessed with the patient Hx  
Assessed with the AUDIT and CAGE 
To ensure that the insomnia is not comorbid with alcoholism or substance abuse  
 
Use of CNS active medications that are for treatment of insomnia or are thought to have caused insomnia as a side 
effect 
Assessed by self-report  
To ensure that the clinical effects observed in this study are not obscured by other medications   
 
Inadequate language comprehension  
Assessed informally by the Clinical Research Coordinator during Intake Interview  
To ensure the quality of self-report data as all the measures are in English.  
 
Current or past experience with CBT-I 
Assessed with patient Hx 
To evaluate why CBT-I was potentially unsuccessful in the past  
 
No access to the computers, I-Pads, or the internet  
Since the primary recruitment methods are via the internet, this is likely to be a non-issue.  
 
c. Subject Recruitment  
A broad strategy will be employed to recruit subjects so that our annual recruitment goals can be met or exceeded. The 
primary methods will be use of our volunteer database (presently more than 3500 individuals), ResearchMatch, Craigslist, 
and an Electronic Medical Records (EMR) query through the University of Pennsylvania Data Analytics Center (DAC). DAC 
EMR data consists of individuals diagnosed with Insomnia and/or individuals who have receive one or more prescriptions 
for Insomnia. These strategies will be supplemented with local advertisements on cable TV, radio, city newspapers, local 
sleep centers, recruitment boards on Penn’s campus, other community centers (e.g., senior citizen living centers), and 


places of business (e.g., restaurants).  All recruitment emails will be sent via REDCap’s utility for group emails, and no 
individual will ever be contacted more than three times.  
 
Additionally, compensation will be pro-rated for each component of the study for a total of $500 per participant. 
Specifically, each participant will receive $50 for completing the screening visit, $25 for fully completing baseline sleep 
diaries, $200 for fully completing all sleep diaries and questionnaires during the treatment period (8 weeks), $100 for 
completing the study, and $125 for completing the follow-up assessment.  
 
d. Duration of Study Participation 
All subjects will be monitored for 2 weeks prior to treatment, for 8 weeks during treatment, and for 2 weeks following 
treatment. Subjects receiving solriamfetol will take medication at 2pm daily for 4 weeks. Medication use will also include 
a 1-week placebo run-in and a 3-week placebo “run-out” (8 weeks’ total). Additionally, follow-up questionnaires will be 
completed 3 months after end of treatment (Insomnia Severity Index [ISI] and Retrospective Sleep Continuity Assessment 
Questionnaire [RSCAQ]). 
 
 
e. Total Number of Subjects and Sites  
40  subjects recruited and completed Phase-1 at one site (Penn).  
 
f. Vulnerable Populations:  
The study does not involve any of the following populations:  
• 
Pregnant women  
• 
Fetuses or neonates 
• 
Prisoners 
• 
Children  
 
No subjects, including the economically disadvantaged, employees, and/or students at Penn, will be unduly influenced, 
encouraged, or coerced into participating in this study. These populations will not be targeted or excluded. IF they are 
encountered and would like to participate, the appropriate measures will be taken in order to allow them the opportunity 
to provide consent.  
 
7. Study Intervention (Study drug, device, biologic, vaccine, food etc.) 
Solriamfetol, 75mg 
 
a. Description 
Solriamfetol (trade name Sunosi), is a norepinephrine-dopamine reuptake inhibitor available in 75mg and 150mg tablets 
for oral administration during the day. Solriamfetol’s primary indication is to treat excessive daytime sleepiness (EDS) in 
patients diagnosed with OSA or Narcolepsy. It binds to the dopamine transporter and the norepinephrine transporter with 
affinities (Ki) of 14.2 μM and 3.7 μM, respectively), does not undergo significant metabolism in humans, and has a Tmax 
of ~2 hours (range 1.25–3.0 hours) and a T1/2 of ~7.1 hours. The pharmacokinetic profile of solriamfetol, along with the 
absence of active metabolites, makes it unlikely that there are accumulation effects with multiple doses over days. See 
the attachment for a copy of the package insert for solriamfetol.  
 
b. Intervention Regimen 
A 2x2 mixed model design. The two factors will be 1) treatment (+/- solriamfetol and +/- CBT-I) and 2) Time (pre-post 
assessment, with additional follow-up data). Patients with insomnia will be randomly assigned to treatment condition. 
 
c. Receipt  
Solriamfetol will be provided (at no cost) by Axsome, and managed by, the Investigational Drug Services of the University 
of Pennsylvania.  
 
d. Storage 
Formulation and storage will be accomplished by Investigational Drug Services of the University of Pennsylvania. 
 
e. Preparation and Packaging 
An over encapsulation technique will be used to ensure that the drug doses and placebo formulations appear identical. 
Over encapsulation will be accomplished by using green and yellow capsules. While over encapsulation may slow the 
absorption of study medication, this should not pose a risk to participants nor compromise the experimental design as the 
slower absorption is constant to condition. Treatment will consist of 75mg of solriamfetol or one or more of inactive 
ingredients in solriamfetol tablets (hydroxypropyl, cellulose, and magnesium stearate.). All subjects will be instructed to 


take the medication or placebo at 2pm for 4 weeks. IDS will create blister packs for each patient that are identical and will 
allocate active medication and placebo according to treatment condition. This will enable double blinding of the study. All 
doses will be over-encapsulated, and all daily doses will be delivered as a single capsule. The use of blister packs will also 
allow us to not only track adherence but to identify the patterning of medication use.  
 
f. Blinding 
Blinding will be accomplished by the Investigational Drug Services (IDS) of the University of Pennsylvania. As noted above, 
placement of medication will be coded per pack (so as to allow for the post hoc assessment of which nights of the week 
were medication and which were placebo). 
 
g. Administration and Accountability    
The study CRC will dispense and receive the foil packs. The pattern of used and unused medication will be captured by 
xeroxing or photographing each foil pack.  Once a subject has completed their participation in the study (i.e., they have 
either completed the study, experienced treatment non-response or relapse, or withdrew from the study) they will be 
given the option to either (a) come to our office at 3535 Market St. and return the blister packs to the CRC, who will bring 
them to IDS for destruction or (b) take the blister-packs to a local pharmacy and record a video of themselves placing the 
blister-packs in a safe drug disposal box, and share the video with study staff. This can be done via email or by uploading 
the video via REDCap (see example link: https://redcap.med.upenn.edu/surveys/?s=XE4T3MKRTPNL7JY7). The video will 
not include the subject’s face or other identifying information. This will ensure that the medication is properly disposed 
of, and that this disposal is documented. Note: the study’s informed consent already mentions that we cannot guarantee 
the security of email correspondence, and that email privacy is based on the email provider’s user agreement. We will 
remind subjects of this so they can consider this factor when deciding whether to return the medication to our office (no 
video required) or to their local pharmacy’s drug disposal box (video required).  
 
h. Subject Compliance Monitoring 
Pill use will be tracked per week via the sleep diary. These data will be compared to, and corroborated with, the foil pack 
data.  
 
i. 
Return or Destruction of Investigational Product 
Blister packs will be returned once the subject has completed the study. Following the archiving of the pill pack (pill 
utilization pattern captured by xeroxing or photograph) the study CRC will return the foil packs and remaining capsules to 
Investigational Drug Services of the University of Pennsylvania for destruction. 
  
8. Study Procedures 
All subjects will receive medication and complete daily sleep diaries and weekly questionnaires.  
 
Does your study use MRI? (CAMRIS is the appropriate contact for all studies involving MRIs) 
 Yes  
 
 No 
 
 
Check of all that apply: 
 1.5T MRI 
 3T MRI 
 7TMRI 
 
Does the MRI use investigational sequences and/or coils? 
(See Experimental Device Clause) 
  
 Yes  
 
 No              
 Unsure   
 
Does your study include pregnant women? 
(See Pregnancy Clause and Justification) 
 
 Yes  
 
 No 
 
Does the MRI require the use of Contrast Agents?  
(See Contrast Risks) 
 
 Yes  
 
 No 
 


Does your study involve the exposure to radiation, radiotracers and/or radiological imaging modalities?  
 
 Yes  
 
 No (If No, no RRSC review is needed)  
 
 
Will any of the radiation exposure result from procedures that are or could be performed solely as a result of a subject’s 
participation in the research protocol? 
 Yes  
 
 No 
 
The following are examples of procedures involving ionizing radiation: 
(Refer to appendix 17.3 for radiotracers, radiation use and 17.5 for nuclear medicine guidance and language) 
 
• 
X-rays (examples: CT scan, chest x-ray, hand/wrist x-ray, abdomen x-ray, DEXA, pQCT, Fluoroscopy/Angiography) 
 
• 
Nuclear Medicine scans (examples:  FDG-PET, PET/CT, Tc-99m, SPECT, MUGA, bone scan) 
 
If you are unsure please contact Will Davidson in EHRS (wed@ehrs.upenn.edu). 
 
Ultrasound  
 Yes  
 
 No 
 
 
Will your study be using CT Scans? (CACTIS is the appropriate contact for studies involving CT scans)  
 Yes  
 
 No 
 
Check off all of the following procedures that will be performed in your research- each option you select will link to the 
template language document:   
 Apheresis/plasma exchange  
 Leukapheresis  
 Bone Marrow Biopsy or Aspirate  
 Use of AP clinical specimens  
 Biopsies- check those which apply  
 
 Blood draw  
 
a. Screening  
• 
Informed Consent  
• 
Questionnaires  
• 
Two weeks of prospective assessment with sleep diaries 
• 
PCP assent  
• 
Home Sleep Apnea Testing (HSAT, type 3 or 4 sleep study) 
 
b. Study Intervention Phase 
See section 3.0 – Investigation Plan.  
 
c. Rescue Therapy [if applicable] N/A 
 
d. Unscheduled Visits 
All subjects may contact the study coordinator at any time by email or phone to make an appointment or to discuss 
questions or concerns.   
 
e. Subject Withdrawal  
Subjects may withdraw from the study at any time without impact to their care. They may also be discontinued from the 
study at the discretion of the Investigator for lack of adherence to intervention or study procedures or visit schedules, 
AEs, or due to medication use. The Investigator or the Sponsor (if applicable) may also withdraw subjects who violate the 
study plan, or to protect the subject for reasons of safety or for administrative reasons.  It will be documented whether 
or not each subject completes the clinical study. Subjects who withdraw early will have one final visit to collect 
investigational product and to follow up regarding adverse events.  
 


i. Data Collection and Follow-up for Withdrawn Subjects 
“Subjects who withdraw consent to participate in the study will be asked to return their foil packs. Please see section 5g”.  
 
f. Early Termination Visits   
See section; Subject Withdrawal 
g. Subject Contact   
Subjects will be contacted through phone, email, and via HIPAA compliant Zoom. Identifying information, such as names, 
will not be used. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. Study Evaluations, Measurements, and Schedule   
 
a. Medical Record Review 
 
 
N/A 
 
b. Physical Examination   N/A. Physician Assent will be ascertained. 
 
c. Vital Signs    N/A. Physician Assent will be ascertained. 
 
d. Laboratory Evaluations 
The primary lab evaluation at screening is the Home Sleep Apnea Testing (HSAT, type 3 or 4 sleep study).   
 
e. Pregnancy Testing  
 
An effective method of birth control (as determined by their physician and intake) is required for women who are pre-
menopausal. There are no requirements regarding the specific form of contraception that must be used. Subjects must 
agree to continue to use this method of birth control during the entire course of the study. If a subject does become 
pregnant during the study, they will be disenrolled. Outcome data on incidental pregnancies will not be collected. 
 
f. Other Evaluations, Measures 
 
N/A 
 
g. Efficacy Evaluations 
The primary efficacy evaluation is accomplished with on-line prospective sampling, e.g., daily sleep diaries and the 
completion of weekly questionnaires.   
 
h. Pharmacokinetic Evaluation 
 
N/A  
 
i. 
Genetic Testing (only if applicable) N/A 
 
j. 
Safety Evaluations 
As noted above, side effects will be assessed in several ways: daily assessments via the sleep diaries and weekly evaluation 
with a medical symptom checklist (52 symptoms where positive endorsements allow subjects to rate their average severity 
and number of days affected).  
 


10. Statistical Plan 
 
k. Primary Endpoint 
The primary endpoint is total wake time (time spent awake in bed) at the end of post-treatment, as measured via a web 
based self-report Sleep Diary. 
l. 
Secondary Endpoints  
1. Patients treated with CBT-I will have significantly greater improvements in sleep continuity from baseline 
to post-treatment compared to patients not administered CBT-I.  
2. Patients treated with CBT-I in combination with solriamfetol with have significantly greater improvements 
in sleep continuity from baseline to post-treatment compared to patients treated with CBT-I alone.  
3. Exploratory hypotheses: Patients treated with CBT-I in combination with solriamfetol will have significantly 
greater adherence with sleep restriction (i.e., sleep rescheduling, prescribed time to bed [PTTB]) and on 
daytime performance measures (e.g., ESS, FSS, etc.) compared to CBT-I alone. 
 
m. Sample Size and Power Determination  
To detect a clinically significant difference in self-reported total wake time of 30 minutes between the four treatment 
groups at the end of post-treatment using an ANOVA test, this study will require 10 subjects per group x 4 groups = 40 
treatment completers. These calculations assume a standard deviation in total wake time of 19 minutes, with 80% power 
to detect the clinically significant change at an alpha level of .05. A total of 60 subjects will be recruited to obtain a sample 
of 40 subjects that complete the study due to attrition. 
 
n. Statistical Methods 
Primary analyses will be conducted on an intention to treat basis and the trial conducted and reported according to 
CONSORT guidelines. Variable distributions will be examined to investigate homoscedasticity, outliers and normality, and 
corrected where appropriate using data transformations. The primary analysis is a 4(condition: +/- solriamfetol and +/- 
CBT-I) x 2(time: pre- and post-treatment) mixed ANOVA on absolute and percent change in total wake time ([TWT], time 
spent awake per night). If the interaction between condition and time is significant, Dunnett multiple comparisons will be 
conducted to further investigate differences in TWT between active treatment conditions versus the control condition to 
test Hypotheses 1-3. These analyses will be unadjusted in the first instance and then adjusted for covariates (primarily, 
age and sex).  
An interim unadjusted analysis as per above will be conducted after 50% of the target sample have completed post-
treatment (i.e., when N=20). 
Secondary analyses include examining the interaction between treatment condition and time on other outcomes, 
including sleep continuity assessed via Sleep Diary (SL, WASO, EMA, TST, SE), insomnia (ISI), daytime sleepiness (ESS and 
KSS), fatigue (FSS and modified KSS), and daytime function (FOSQ-10, POMS, and PVT). Additionally, compliance to the 
medication (adherence to daily pill administration, as assessed via blister packs) and to sleep restriction (adherence to 
prescribed time to bed) will be investigated as covariates. 
 
i. Baseline Data 
Baseline and demographic characteristics will be summarized by standard descriptive statistics (including mean and 
standard deviation for continuous variables such as age and standard percentages for categorical variables such as 
gender). 
 
ii. Pharmacokinetic Analysis 
 
N/A 
 
iii. Interim Analysis  
 
 
N/A 
 
iv. Safety Analysis  
Side effects and adverse events will be assessed in several ways: daily assessments via the sleep diaries, and with a weekly 
evaluation using a medical symptoms checklist (52 symptoms where positive endorsements allow subjects to rate their 
average severity and number of days affected), 
 


An adverse event will be defined as 1) any behavioral or health complaint spontaneously reported during the study, 2) an 
above threshold score on the study clinical assessment instruments (ESS, PHQ-9, or GAD-7), and/or a 20% increase in the 
medical symptom check list scores (frequency or severity). 
 
o. Subject Population(s) for Analysis 
• All-randomized population. 
• All-treated population 
• Protocol-compliant population 
 
11. Safety and Adverse Events (as stated in the IRB template) 
p. Definitions 
i. Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity during the course 
of the study. Illnesses or injuries will be regarded as adverse events.  Abnormal results of diagnostic procedures are 
considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
ii. Serious Adverse Event 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening but are clearly of major clinical 
significance.   They may jeopardize the subject and may require intervention to prevent one of the other serious outcomes 
noted above.  For example, drug overdose or abuse, a seizure that did not result in in-patient hospitalization, or intensive 
treatment of bronchospasm in an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious adverse events. 
 
q. Recording of Adverse Events 
At each contact with the subject, the investigator will seek information on adverse events by specific questioning and, as 
appropriate, by examination. Information on all adverse events will be recorded immediately in the source document, and 
also in the appropriate adverse event module of the case report form (CRF).  All clearly related signs, symptoms, and 
abnormal diagnostic procedures results will be recorded in the source document, though grouped under one diagnosis. 
All adverse events occurring during the study period will be recorded.  The clinical course of each event will be followed 
until resolution, stabilization, or until it has been determined that the study intervention or participation is not the cause.  
Serious adverse events that are still ongoing at the end of the study period will be followed up to determine the final 
outcome.  Any serious adverse event that occurs after the study period and is considered to be possibly related to the 
study intervention or study participation will be recorded and reported immediately. 
 
r. Relationship of AE to Study  
The relationship of each adverse event to the study procedures will be classified in terms of the event’s potential 
relationship to the study (definitely related, probably related, possibly related, unlikely or unrelated). 
 
s. Reporting of Adverse Events, Adverse Device Effects and Unanticipated Problems 
The occurrence of adverse events will be reported to the study’s medical collaborators, advisory board chair, Penn IRB, 
and our contacts at Axsome.  
 
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of the initial report 
includes: 


• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study intervention was discontinued 
• 
The reason why the event is classified as serious 
• 
Investigator 
assessment 
of 
the 
association 
between the event and study intervention 
 
Additionally all other events (unanticipated problems, adverse reactions, unanticipated adverse device effects and subject 
complaints  will be recorded and reported with respect to institutional and federal policies as described in the Penn 
Manual and below. 
 
i. Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that changes the investigator’s 
assessment of the event, a follow-up report including all relevant new or reassessed information (e.g., concomitant 
medication, medical history) will be submitted to the IRB. The investigator will be responsible for ensuring that all SAE are 
followed until either resolved or stable. 
 
ii. Investigator reporting: notifying the study sponsor 
Any study-related unanticipated problem posing risk to subjects or others, and any type of serious adverse event, will be 
reported to the study sponsor (Axsome) by telephone and email within 24 hours of the event. Specifically, the SAE will be 
reported to our program officer. “To report such events, a Serious Adverse Event (SAE) form will be completed by the 
investigator and faxed to the study sponsor within 24 hours.  The investigator will keep a copy of this SAE form on file at 
the study site.  Report serious adverse events to the therapist, CRC, and/or the PI via e-mail or phone 
 
Study PI: Michael Perlis, mperlis@upenn.edu,  
CRC: Mark Seewald, mark.seewald@pennmedicine.upenn.edu 
 
Within the following 48 hours, the investigator will provide further information on the serious adverse event or the 
unanticipated problem in the form of a written narrative.  This will include a copy of the completed Serious Adverse Event 
form, and any other diagnostic information that will assist the understanding of the event.  Significant new information 
on ongoing serious adverse events will be provided promptly to the study sponsor. 
t. Investigator Reporting: Notifying the Penn IRB  
Penn IRB will be notified in accordance with the requirements and timelines as specified by the IRB.  
 
i. Sponsor reporting: Notifying the FDA (applies only to Penn sponsor –investigator IND/IDE holders)  
 
 
 
 
 
 
N/A  
 
ii. Sponsor reporting: Notifying participating investigators  
N/A 
 
u. Unblinding Procedures 
In the event of an SAE, Investigational Drug Services of the University of Pennsylvania will unblind the subject’s status with 
respect to treatment condition. This information will be provided to the subject, and with permission, the subject’s clinical 
providers (or emergency care providers) within 24 hours or less.  
 
v. Stopping Rules  
The advisory board chair will be notified of any serious adverse events that occur, regardless of whether they are thought 
to be study-related, within 24 hours of project staff learning of their occurrence. The advisory board chair will decide, 
independent of the study investigators, whether the study should be discontinued.  
 
w. Medical Monitoring 
The medical monitoring will be accomplished by our collaborating physician, Dr. Michael Thase.  
 
i. Data and Safety Monitoring Plan 
Please see below. 
 
Data Safety Monitoring Board   
We will establish a four-person advisory board comprised of a second MD sleep medicine specialist, clinical psychologist, 
a nurse sleep scientist, and a biostatistician. Membership consists of persons completely independent of the investigators 
who have no financial, scientific, or other conflicts of interest with the trial. Collaborators of the PIs will not be eligible to 


serve on the advisory board. The board will receive reports from the study team every six months with information about 
the progress of recruitment, the demographic characteristics of participants, serious adverse events, the number of 
dropouts, and participants’ reasons for dropping out, and any protocol amendments. These meetings will focus on the 
conduct and progress of the study, including participant accrual, protocol compliance, and problems encountered.  
 
12. Study Administration, Data Handling and Record Keeping 
 
x. Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  In the event that a subject revokes 
authorization to collect or use PHI, the investigator, by regulation, retains the ability to use all information 
collected prior to the revocation of subject authorization.  For subjects that have revoked authorization to collect 
or use PHI, attempts will be made to obtain permission to collect at least vital status (i.e. that the subject is alive) 
at the end of their scheduled study period. 
 
In the case of the present study all self-report data will be acquired through RedCap and Hypknowledge. Files 
containing PHI (that is not stored in the EMR) will be stored on a secure shared drive on the Penn Network. Only 
authorized study staff will have access to this shared drive. 
 
y. Data Collection and Management  
All data will be collected via  Redcap and Hypknowledge.   Data download will only be available to the PI and/or his 
designates. Files containing PHI will be stored on a secure shared drive on the Penn network. Only authorized study staff 
will have access to this shared drive.  
 
z. Records Retention  
All electronic data will be maintained for a period equal to that required by the study sponsor. Longer term database 
management will occur, but all subject identifiers will be removed.  
 
13. Study Monitoring, Auditing, and Inspecting 
The study materials and databases will be available to the study sponsor, the advisory board, and/or Penn IRB should a 
data audit be deemed necessary.  
 
aa. Study Monitoring Plan 
See DSMB section.  
 
bb. Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the sponsor, government 
regulatory bodies, and University compliance and quality assurance groups of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.).  The investigator will ensure the 
capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). Participation as 
an investigator in this study implies acceptance of potential inspection by government regulatory authorities and 
applicable University compliance and quality assurance offices. 
 
14. Ethical Considerations 
This study is to be conducted in accordance with applicable US government regulations and international standards of 
Good Clinical Practice, and applicable institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics Committee (EC) or 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the study conduct.  The 
decision of the EC/IRB concerning the conduct of the study will be made in writing to the investigator and a copy of this 
decision will be provided to the sponsor before commencement of this study. 
 


cc. Risks 
Risks of Cognitive Behavioral Therapy for Insomnia (CBT-I): 
CBT-I may result in temporary increases in daytime fatigue and/or sleepiness, and/or memory and 
concentration difficulties. 
dd. Risks of Solriamfetol: 
The most commonly observed side effects of Solriamfetol are headache, nausea, dizziness, palpitations, 
abdominal pain, feeling jittery, chest discomfort, decreased appetite, anxiety, insomnia irritability, dry 
mouth, and diarrhea. These effects generally happen with an incident rate of <2%. Headaches however 
were found to occur in up to 5% of patients using the medication (these are placebo-adjusted rates).  
Please note that solriamfetol can cause increased blood pressure, heart rate, increased risk for 
exacerbation of bipolar disorder and/or psychosis. Physician assent will be obtained prior to enrollment 
and any subjects who present with the aforementioned medical and/or psychiatric diagnoses will be 
excluded.  
 
12.1.1 Possible Drug Interactions 
 
 Possible drug interactions with solriamfetol include: 
 
• 
MAOIs (must have stopped the medication > 14 days ago) 
 
ee. Benefits 
As indicated in the research plan, participants in this study will likely experience improved sleep (less insomnia). The results 
of this study, it is hoped, will provide a novel approach to the treatment of insomnia that is as or more effective than 
traditional approaches and/or makes traditional treatments easier to follow. 
 
ff. Risk Benefit Assessment 
 
1. Risks:  
Non-invasive procedures are proposed. It is possible that completion of questionnaires may cause some 
discomfort for participants due to the content of questions asked. Subjects may experience higher than normal 
levels of sleepiness due to the nature of CBT-I. The use of the internet for completion of study measures also 
introduces potential risks for confidentiality of personal data. 
 
2. Benefits: 
There may be no known benefits for participants in this study. This project serves to benefit the research 
community by providing data on insomnia treatment mechanisms. Subjects may experience a decrease in their 
insomnia and fatigue symptoms. The risks to the participants are believed to be outweighed by the benefit of 
conducting the research. 
 
10. Informed Consent Process / HIPAA Authorization  
 
Overview 
Consent is done on an individual basis during the initial evaluation by a designated staff member via HIPAA compliant 
Zoom. Subjects will be asked to complete the consent in a private area. For the informed consent process, the details of 
the consent form are discussed, and the subject is encouraged to ask questions about study participation and any other 
details described in the consent form. Once signed, the subject is provided a copy of the consent form to keep. 
 
Children and Adolescents  
N/A 
 
Adult Subjects Not Competent to Give Consent 
Only competent adults will be included in this study. 
 


i. 
Alterations to Typical Consent Process (only include if applicable) N/A 
 
1. Waiver of Consent (In some cases for screening/portions of that study that qualify as minimal risk, a waiver of 
documentation of consent may be permissible per IRB SOPs)  N/A 
 
2. Waiver of Written Documentation of Consent  N/A 
 
3. Waiver of Written Documentation of Consent where the research is subject to FDA regulations  N/A 
 
4. Waiver of HIPAA Authorization  N/A 
 
j. 
Study Finances 
 
a. Funding Source 
This study is supported by an Axsome Pharmaceuticals 
 
b. Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on Conflicts of Interest 
Related to Research.  
 
c. Subject Stipends or Payments 
d. Compensation will be pro-rated for each component of the study for a total of $500 per participant. 
Specifically, each participant will receive $50 for completing the screening visit, $25 for fully completing 
baseline sleep diaries, $200 for fully completing all sleep diaries and questionnaires during the treatment 
period (8 weeks), $100 for completing the study, and $125 for completing the follow-up assessment.  
 
k. Publication Plan 
While the primary intent of the study is to garner effect size data, if the inferential statistics are significant with 5-8 subjects 
per condition, the data will be summarized as a short report for the journal SLEEP or the Journal of Sleep Research. 
 
l. 
References 
Relevant references were placed in text (PMID numbers). Also below.  
 
1: 1. Perlis, M., Jungquist, C., Smith, M. T., & Posner, D. (2005). The cognitive behavioral treatment of insomnia: A 
treatment manual. Springer. ISBN-10: 0387222529, https://www.amazon.com/Cognitive-Behavioral-Treatment-
Insomnia-Session-ebook/dp/B000PC6BGA 
 
m. Attachments 
• Sample Consent Form 
 
a. Source Documents 
The data is being acquired on-line. The original questionnaires are not retained, though they can be regenerated from the 
database data.   
 
b. Case Report Forms (CRFs) 
The data is being acquired on-line. The original questionnaires are not retained, though they can be regenerated from the 
database data.   
 
 
 
 
 
 
 
 
 
 
 
 
 

ICF_001.pdf: 
Official Study Title: Three Approaches to Maintenance Therapy for 
Chronic Insomnia in Older Adults 
NCT Number: NCT03774810
Date: 06/01/2021
Cover Page


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UNIVERSITY OF PENNSYLVANIA 
RESEARCH SUBJECT 
INFORMED CONSENT AND HIPAA AUTHORIZATON FORM 
Protocol Title: 
Three Approaches to Maintenance Therapy for 
Chronic Insomnia in Older Adults 
Principal 
Investigator: 
Michael Perlis, Ph.D. 
3535 Market Street, Suite 670 
Philadelphia, PA 19104 
mperlis@upenn.edu 
215-746-3578
Emergency 
Contact: 
Medical Resident on Call 
215-662-8000
Why am I being asked to volunteer? 
This consent form describes a research study and what you may expect if you decide to participate. 
You are encouraged to read this consent form carefully and to ask the person who presents it any 
questions you may have before making your decision whether or not to participate. You are being 
asked to participate in this research study because you have persistent trouble sleeping (insomnia) at 
night. This form describes the known possible risks and benefits of the study. You are completely 
free to choose whether or not to participate in this study. 
You are being invited to participate in a research study. Your participation is voluntary which means 
you can choose whether or not you want to participate. If you choose not to participate, there will be 
no loss of benefits to which you are otherwise entitled. Before you can make your decision, you will 
need to know what the study is about, the possible risks and benefits of being in this study, and what 
you will have to do in this study. The research team is going to talk to you about the research study, 
and they will give you this consent form to read. You may also decide to discuss it with your family, 
friends, or family doctor. You may find some of the medical language difficult to understand. Please 
ask the study doctor and/or the research team about this form. If you decide to participate, you will be 
asked to sign this form. 


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What is the purpose of this research study? 
The purpose of this study is to determine whether insomnia symptoms can be managed with smaller 
amounts of medication than are commonly used among those who are treated with zolpidem. 
 
How long will I be in the study?  
Your active participation will last for a maximum of 54 weeks, including a 2-week baseline (no 
medication), 4 weeks of nightly zolpidem, 12 weeks of full dose (nightly), intermittent dosing (1-3 doses 
per week), or one of two forms of variable dosing, and 36 weeks of extended treatment.  
 
How many other people will be in the study? 
200 subjects from the local community are expected to complete this study. Recruitment will take place 
over 3-4 years’ time.  
 
What am I being asked to do?  
If you decide to participate, there are a total of four study phases that you may be asked to complete. 
The four phases are described below. 
 
Phase-1:  
 
Initial Evaluation. This evaluation occurs at the offices of the Behavioral Sleep Medicine Program (Suite 
670, 3535 Market Street Philadelphia, PA 19104) or via a virtual visit (via Blue Jeans) and lasts about 1 
to 2 hours. Procedures include: 
 
• Completing forms asking questions about your sleep, mood, alcohol use, medical history, your 
current medications, and background questions about your age, race, and education.  
 
• The provision of your consent to contact your primary care provider to gain their assent 
(agreement) that you may participate in the trial safely.  
 
The information obtained during the initial assessment will be used to see if you are eligible to 
participate in this study. If you are determined ineligible, you will not be able to continue in the study 
but will be provided with a referral if appropriate. 
 
NOTE: This study will be using an Internet Data Portal (IDP) system to collect most questionnaire 
data. The IDP is a Research Electronic Data Capture and is a secure web application. It is a password 
protected site located on Penn’s servers in which the data will live in a database online where only 
qualified research personnel can access it. During the initial evaluation you will be introduced to 
this system and provided with a username and password. The study staff will assist you in filling 
out the questionnaires using this IDP system. 
 
Phase-2: Baseline Period. This phase lasts 14 days. Your participation includes: 
 
• Completing daily sleep diaries at home. The online diary form requires about 5 minutes each day 


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to complete.  
 
• Completing 6 to 7 forms asking questions about your medical symptoms, and sleep each week of 
the baseline period. These online questionnaires require about 15 minutes to complete.   
 
• Abstaining from the use of any medication or over the counter product that is used expressly for 
the purpose of helping you fall or stay asleep (e.g. trazadone/desyrel, melatonin, nyquil, tylenol 
PM, Benadryl, etc.). If you choose to discontinue your current sleep medication to participate in 
our study, please do this in consultation with the clinician that prescribed your sleep medication. 
Please note that discontinuation of your current sleep medication will make it necessary to extend 
the baseline component of our study by at least two weeks.   
 
Should the sleep diaries indicate that your insomnia is not of the type, severity, or frequency required 
for the study, you will not be able to continue in the study but will be provided with a referral. This 
referral will be for the Penn Sleep Disorder Center. If you or study personnel deem your two weeks to 
be unusual, you may be offered the chance to repeat the baseline period. 
 
Phase-3: Sleep Lab Study (polysomnography) or Home Sleep Apnea Test (HSAT). You will undergo a 
polysomnography study or an HSAT to determine if you are eligible to continue in the study. During the 
pandemic all sleep tests will be administered at home. After the pandemic, the study investigators will 
decide which type of study you will receive. Both sleep assessments will last for 1 night.  
 
The HSAT equipment will be shipped to your house. A member of the study team will contact you to 
go over proper use instructions. On the night of the test, you can go to bed at your regular bedtime. 
Prior to bedtime, you will attach the sensor(s) as instructed and start the test. Upon waking up, you 
will stop the test and remove the sensor(s). On the day immediately following the sleep test, you will 
ship the device back in the prepaid shipping envelope  
 
Procedures for the polysomnography study are: you will be asked to arrive at the sleep lab located at 
the Hospital of the University of Pennsylvania (HUP) at the cross streets of 34th and Spruce by 7 P.M. 
for a polysomnographic study (PSG). Upon arrival, to ensure for accurate laboratory measurements, 
urine toxicology screens may be performed to rule out illegal substance use. These data are acquired 
to explain abnormal findings on the PSG. Following the sleep study, it will be determined whether a 
repeat study is necessary based on the findings both from the clinical chemistries and the 
polysomnography. If a repeat study is necessary, one of the project investigators will discuss the issue 
of substance use with you to: (1) determine if the clinical chemistries’ finding was an error (for example 
poppy seeds led to a positive screen) or (2) gain your willingness to refrain from substance use for the 
second PSG and for the remainder of the study. If you screen positive a second time, your participation 
will be discontinued.   
 
The specific procedure for a PSG requires that you have a set of sensors placed on your face, scalp, and 
body by a technician. All the sensors are attached with surgical tape, paste and glue. The sensors on 
your face are attached on your left and right temple, cheek bone and under your nose. The sensors 
on the temple and cheek bone measure eye movements associated with falling asleep and dreaming. 
The sensors under your nose measure airflow through your mouth and nose. The sensors on your scalp 


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measure brain waves during sleep. The sensors on the body are placed above the collar bones and over 
the calf muscles. The sensors over the collar bones measure heart muscle activity. The sensors over 
the calf muscles measure muscle activity from the legs. In addition, a strap will be placed around your 
chest and abdomen to measure respiration. 
 
After you have been connected to the equipment, you are expected to stay in bed until final wake time 
the next morning, except for bathroom breaks. You will be visually monitored by the lab technicians by 
remote video. In the morning, you will be awakened by the technician (if needed), be unhooked from 
the equipment, and then allowed to shower, dress, and eat before leaving. You will be free to go about 
your normal schedule for the rest of the day.  
 
If the in-lab PSG sleep or HSAT study finds evidence of a sleep disorder other than insomnia, such as 
sleep apnea, you will not be able to continue in the study but will be provided with a referral. 
 
Phase-4: Standard Treatment. All participating subjects will receive one month of standard nightly 
treatment. If you have a positive treatment response you will remain in the study and be randomized 
to one of the following treatment conditions: nightly dosing, intermittent dosing (1-3 pills week, full 
dose), or one of two variable dose conditions (nightly pill use where any given pill is a variable dose). 
The assignment of condition will be accomplished by a process that is the same as the flip of a coin and 
neither you nor the study personnel will know which condition you have been assigned to (this is 
referred to as a “double blind” study). You will have an equal chance of being randomized to each of 
the 4 study arms. In the case of an emergency, the blind will be broken and the study doctor and 
clinicians associated with your care will be informed of which dosing condition you were assigned to.   
 
Standard treatment will last for 4 weeks. The experimental phase will extend over two periods. The 
first period will last for 12 weeks. The second period will last for 36 weeks. Both periods include:  
 
• Taking a pill 30 minutes prior to bedtime.  
 
In one case, this will involve taking 1-3 pills per week. In the remaining 
conditions, pills will be taken on each and every night. Depending on the specific 
group you are assigned to, you will either receive 10mg or 5mg of zolpidem 
(variable by age and sex) or a variable dose of zolpidem on a nightly basis (range 
from 0 mg to 10 mg per night).  
Please note that the effect of zolpidem may be slowed if taken with or immediately after a meal. 
 
• Completing a sleep diary each day;  
 
• Completing 6 to 7 questionnaires each week;  
 
• A monthly visit to Penn (or tele-visit) to return your medication foil packs and to receive a new foil 
pack with the next month of medication. During this visit, a Nurse Practitioner will ask questions 
regarding your mental and physical health as well as the effectiveness of the treatment so that we 
can optimally track your health and wellbeing.  
 


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If you do not experience a treatment response or (following a treatment response) you experience a 
relapse of insomnia, you will not be able to continue in the study but will be given the opportunity to 
be treated with Cognitive Behavioral Therapy for Insomnia (CBT-I) at no cost. Assessments of your 
clinical status (how your insomnia is responding to treatment) will be based on your daily sleep diaries 
and weekly questionnaires.  
 
During Phase-4, you may be asked to undergo a physical if the nurse practitioner deems it to be 
appropriate and necessary. The physical will involve standard vital measures (e.g., temperature, blood 
pressure, height and weight, etc.) and, based on the judgement of the research clinician, may involve 
an EKG and/or blood and urine chemistries.  
 
What are the possible risks or discomforts?  
Risks associated with taking zolpidem. Zolpidem is an FDA approved medication for insomnia. You 
could experience some of the following side effects: dizziness, daytime drowsiness, headache, nausea, 
or vomiting. Rare cases of severe allergic reactions have been observed, and there have been reports 
of people performing complex behaviors such as preparing and eating food, making phone calls, or 
driving while not fully awake after taking zolpidem. These risks are more likely to happen when 
zolpidem is taken with alcohol or other medications that depress the nervous system, so alcohol should 
be used cautiously during the course of the study. Worsening of depression or suicidal thinking may 
occur. There is also risk of respiratory depression in patients with compromised respiratory function. 
Other unknown side effects could occur and all should be reported to study personnel. Please note 
that withdrawal effects may occur with rapid dose reduction or discontinuation. 
 
Drug Interactions. Zolpidem may interact with the following drugs to cause additional side effects. If 
taken with imipramine, decreased alertness may occur. If zolpidem is taken with chlorpromazine, 
impaired alertness and psychomotor performance may occur. The combination of zolpidem and 
rifampin may lead to a decrease in the efficacy of zolpidem. Lastly, if taken with ketoconazole, the 
effect of zolpidem may be increased. Memory Problems. Sleep medicines may cause a special type of 
memory loss or "amnesia." When this occurs, a person may not remember what has happened for 
several hours after taking this medicine. This is usually not a problem since most people fall asleep after 
taking the medicine. Memory loss can be a problem, however, when sleep medicines are taken while 
traveling, such as during an airplane flight and the person wakes up before the effect of the medicine 
is gone. This has been called "traveler's amnesia." Memory problems are not common while taking 
zolpidem.  
 
If side effects occur that are not controllable or that are too bothersome, you will be free to withdraw 
from the study and you will be referred to a staff physician and/or to your primary care physician for 
follow up care. As with taking any medication, your symptoms may stay the same or even worsen. Our 
staff physician will be available in the event that you have any questions or concerns. 
 
Risks associated with taking zolpidem while pregnant and/or nursing. Because the effects of zolpidem 
on unborn children are currently unknown, you may not participate in this study if you are, or are 
intending to become pregnant, or if you are breast-feeding. If you are a woman, you must meet one or 
more of the following criteria.  


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1. 
Two or more years post-menopause. 
2. 
Surgically sterile (bilateral tubal ligation, hysterectomy or have had both ovaries removed),   
 
If the above does not describe you, then you should be using an effective method of birth control as 
determined by your physician. There are no requirements regarding the specific form of contraception 
that must be used. However,  you must agree to continue to use this method of birth control during 
the entire course of the study. In addition, if you are able to have children, a pregnancy test (urine) 
must be negative prior to entering the study. The test will be administered during Phase 3, the sleep 
study visit, and at subsequent quarter annual history and physical exams during Phase 4 of the study. 
Contact the study coordinator right away if you suspect that you are pregnant. 
 
Risks associated with taking doses lower than those indicated for the treatment of insomnia. Some 
participants will receive lower than normal doses of zolpidem during portions of the study. If you 
receive a lower than normal dose, this may result in no change in your sleep, you may experience some 
insomnia symptoms, or you may experience a level of insomnia that is comparable with, or (in rare 
cases) worse than, what you experienced prior to enrolling in this study. 
 
Risks associated with the questionnaires. Answering some of the questions may make you feel 
uncomfortable. You do not have to answer any questions you do not want to. 
 
Risks associated with polysomnography. Some people experience minor discomfort (dry skin, rash) 
from having the skin cleaned and sensors placed on the skin during the  sleep studies. 
 
What if new information becomes available about the study? 
During the course of this study, we may find more information that could be important to you. This 
includes information that, once learned, might cause you to change your mind about being in the 
study. We will notify you as soon as possible if such information becomes available. 
 
What are the possible benefits of the study?  
The detailed assessment of your sleep (including an in- lab sleep study) may result in the detection 
of factors, or the presence of other sleep disorders, that may account for your insomnia. In these 
cases, you will be provided with a referral and our assessment materials will, upon your request, 
be made available to you to give to your primary care doctor and/or to the specialist to whom you were 
referred. You may or may not experience relief from your insomnia via the treatment provided during 
the study.  
 
What other choices do I have if I do not participate?  
Your alternative to being in the study is to not be in the study. If you choose not to be in the study 
you may want to talk to your personal physician about treatments for sleep problems.  
 
Will I be paid for being in this study?  
• At the end of your intake visit, you will receive $25. 
• For completing a history and physical (H&P), you will receive $25.   


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• For completing the sleep lab study, you will receive $100. 
• For completing the diaries/questionnaires and taking the medication as prescribed you will be paid 
$25 for each monthly visit you complete ($300 total if you complete all 12 study visits). 
 
If you complete all phases of the study you will receive a total of $450 compensation. Compensation 
will be distributed via ClinCard, our participant payment system. Please note that in order to be paid, 
you are required to complete a W-9 form, which includes your social security number.If you receive 
more than $600.00 compensation in one year for participation in research studies at the University of 
Pennsylvania, you must report this as income to the federal government for tax purposes. 
 
In addition to the above payments, a lottery will be conducted once each month and will work as 
follows. Each sleep diary you complete will be counted as an ‘entry’ into the lottery. At the end of each 
month, we will conduct a drawing where random ID’s are “selected” for each of the following prizes: 
4@$50 and 3@$100, 2@$500 and 1@$1000 ($2500 per month / $30,000 per year). You are eligible to 
win one prize per month and one prize of each dollar value over the year (total of 4 awards per person 
is possible). Seven to eight subjects out of every 10 participants will win one or more awards over the 
course of the 12 month period of participation, assuming equal compliance across subjects. At the 
conclusion of the study, a final lottery will be conducted for all participants that have completed the 
study with twenty $500 prizes being awarded through the random drawing. Please note that the use 
of the lottery has been approved by both NIH and the Penn IRB for prior studies by our group.   
 
Will I have to pay for anything? 
There is no cost to you to participate in this research study.  Reimbursement for travel to and from our 
offices is offered as part of your study remuneration. The treatment is provided at no cost to you. You 
and/or your health insurance may be billed for the costs of medical care during this study if these 
expenses would have happened even if you were not in the study, or if your insurance agrees in 
advance to pay. 
 
What happens if I am injured from being in the study?  
If you have a medical emergency during the study you should go to the nearest emergency room. You 
may contact the Principal Investigator or Emergency contact listed on page one of this form. You may 
also contact your own doctor, or seek treatment outside of the University of Pennsylvania.  
 
We will offer you the care needed to treat injuries directly resulting from taking part in this research.  
We may bill your insurance company or other third parties, if appropriate, for the costs of the care you 
get for the injury, but you may also be responsible for some of them. There are no plans for the 
University of Pennsylvania to pay you or give you other compensation for the injury.  You do not give 
up your legal rights by signing this form.  If you think you have been injured as a result of taking part in 
this research study, tell the person in charge of the research study as soon as possible.   
 
When is the Study over? Can I leave the Study before it ends? 
This study is expected to end after all participants have completed all visits, and all information has 


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been collected. This study may also be stopped at any time by your physician, the study Sponsor, or 
the Food and Drug Administration (FDA) without your consent because: 
 
 The Primary Investigator feels it is necessary for your health or safety. Such an action would not 
require your consent, but you will be informed if such a decision is made and the reason for this 
decision. 
 You have not followed study instructions. 
 The Sponsor, the study Principal Investigator, or the Food and Drug Administration (FDA) has 
decided to stop the study. 
 
You have the right to drop out of the research study at any time during your participation. There is no 
penalty or loss of benefits to which you are otherwise entitled if you decide to do so. Withdrawal will 
not interfere with your future care. If you no longer wish to be in the research study, please contact 
the study coordinator, at 215-746-4378 or 215-573-5935 and provide in writing a statement that you 
no longer wish to participate in the study. 
 
Who can see or use my information? How will my personal information be protected?  
The research team will make every effort to keep all the information you tell us during the study strictly 
confidential, as required by law. Any documents you sign, where you can be identified by name will 
be kept in a locked drawer in Dr. Perlis’s office. Other documents containing your study information 
will be identified by a unique code number. These documents will be kept confidential. The Institutional 
Review Board (IRB) at the University of Pennsylvania is responsible for protecting the rights and welfare 
of research volunteers like you. The IRB has access to study information. All the documents will be 
destroyed when the study is over. The answers to the questionnaires that you complete on the 
computer each day will be kept in a secure database that only the study investigators can access. Your 
email address is the only identifying information that will be kept in this file. 
As a reminder of study appointments, some subjects prefer to have contact via email. Email privacy is 
based on the user agreement with your email provider. Please indicate if you are willing to have your 
email used for study contact.      Yes        
No       (circle one) 
We also intend to contact you via text message to remind you of study appointments and procedures. 
Please indicate if you are willing to receive study contact via text message.  
Yes 
 
No
 
(circle one)  
Subject Initials: ____________________ 
Date: ____________________ 
 
 
Finally, you should understand that study staff is not prevented from taking steps, including reporting 
to authorities, to prevent serious harm to yourself or others. 
 
Electronic Medical Records and Research Results 
 


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What is an Electronic Medical Record? 
An Electronic Medical Record (EMR) is an electronic version of the record of your care within a health 
system. An EMR is simply a computerized version of a paper medical record.  
 
A clinical trial management system (CTMS) is used to register your information as a participant in a 
study and to allow for your research data to be entered/stored for the purposes of data analysis and 
any other required activity for the purpose of the conduct of the research.  
 
If you are receiving care or have received care within the University of Pennsylvania Health System 
(UPHS) (outpatient or inpatient) and are participating in a University of Pennsylvania research study,  
information related to your participation in the research (i.e. laboratory tests, imaging studies and 
clinical procedures) may be placed in your existing EMR maintained by UPHS. Information related to 
your participation in clinical research will also be contained in the CTMS. 
 
If you have never received care within UPHS and are participating in a University of Pennsylvania 
research study that uses UPHS services, an EMR will be created for you for the purpose of maintaining 
any information produced from your participation in this research study.  The creation of this EMR is 
required for your participation in this study. In order to create your EMR, the study team will need to 
obtain basic information about you that would be similar to the information you would provide the 
first time you visit a hospital or medical facility (i.e. your name, the name of your primary doctor, the 
type of insurance you have). Information related to your participation in the study (i.e. laboratory tests, 
imaging studies and clinical procedures) may be placed in this EMR.  
Once placed in your EMR or in the CTMS, your information may be accessible to appropriate UPHS 
workforce members that are not part of the research team.  Information within your EMR may also be 
shared with others who are determined by UPHS to be appropriate to have access to your EMR (e.g. 
health insurance company, disability provider, etc.). 
 
Additional Information Regarding your Health Information Privacy (HIPAA)  
What information about me may be collected, used or shared with others?   
As part of our study you will share the following information,  
• 
Name, address, telephone number, date of birth, electronic mail addresses  
• 
Social Security number for compensation purposes 
• 
Personal and family medical history  
•     Results from a physical examinations, tests or procedures 
 
Why is my information being used? 
Your information is used by the research team to contact you during the study. Your information and results of 
tests and procedures are also used to: 
• do the research 
• oversee the research 
• to see if the research was done right 
• to evaluate and manage research functions.   
 
Who may use and share information about me?   


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The following individuals may use or share your information for this research study: 
• 
The study Principal Investigator, Michael L. Perlis PhD  
• 
The study Co-Investigators, Michael Thase MD, Nalaka Gooneratne MD, Knashawn Morales PhD 
• 
The study collaborators, coordinators, research assistants, and administration  
  
Ivan Vargas PhD 
  
Yoon Chang MD 
  
Mark Seewald BS (Coordinator)  
 
  
Waliuddin Khader BA (coordinator & programmer) 
  
Eileen Mergliano BA (research business administrator) 
  
Josh Giller BS (research assistant) 
  
Alexandria Muench PsyD (postdoctoral fellow) 
• 
Other research personnel with access to the databases for research and/or study coordination and as 
otherwise approved by the IRB 
 
Who, outside of the School of Medicine, might receive my information?  
Our collaborator from Harvard University  
Our program officer from NIH (NIA)  
 
 
 Oversight organizations 
 
 The Office of Human Research Protections 
 
 The study data and safety monitoring board 
 
 
 
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required by U.S. Law. 
This web site will not include information that can identify you. At most, the web site will include a summary 
of the results. You can search this web site at any time. 
Once your personal health information is disclosed to others outside the School of Medicine, it may no longer 
be covered by federal privacy protection regulations.   
The Principal Investigator or study staff will inform you if there are any additions to the list above during your 
active participation in the trial. Any additions will be subject to University of Pennsylvania procedures 
developed to protect your privacy. 
 
How long may the School of Medicine use or disclose my personal health information?   
Your authorization for use of your personal health information for this specific study does not expire.  
 
Your information may be held in a research database.  However, the School of Medicine may not re-use or re-
disclose information collected in this study for a purpose other than this study unless: 
• 
You have given written authorization  
• 
The University of Pennsylvania’s Institutional Review Board grants permission 
• 
As permitted by law  
 
Can I change my mind about giving permission for use of my information? 


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Yes. You may withdraw or take away your permission to use and disclose your health information at any time.  
You do this by sending written notice to the investigator for the study.  If you withdraw your permission, you 
will not be able to stay in this study. 
 
What if I decide not to give permission to use and give out my health information? 
Then you will not be able to be in this research study. 
 
You will be given a copy of this Research Subject HIPAA Authorization describing your confidentiality and 
privacy rights for this study.  
 
By signing this document you are permitting the School of Medicine to use and disclose personal health 
information collected about you for research purposes as described above. 
 
Who can I call with questions, complaints or if I’m concerned about my rights as a 
research subject? 
 
If you have questions, concerns or complaints regarding your participation in this research study or if 
you have any questions about your rights as a research subject, you should speak with the Principal 
Investigator listed on page one of this form. If a member of the research team cannot be reached 
or you want to talk to someone other than those working on the study, you may contact the 
Office of Regulatory Affairs with any question, concerns or complaints at the University of Pennsylvania 
by calling (215) 898-2614. 
 
When you sign this form, you are agreeing to take part in this research study. This means that you 
have read the consent form, your questions have been answered, and you have decided to volunteer. 
Your signature also means that you are permitting the University of Pennsylvania to use your 
personal health information collected about you for research purposes within our institution. You 
are also allowing the University of Pennsylvania to disclose that personal health information to 
outside organizations or people involved with the operations of this study. 
A copy of this consent form will be given to you. 
 
 
Name of Subject (Please Print) 
 
Signature of Subject 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Person Obtaining Consent (print) 
 
Signature of POC 
 
Date