Clinical trial NCT02638168
Conditions: Attention Deficit Disorder With Hyperactivity Behavioral Insomnia of Childhood
Sponsor: Milton S. Hershey Medical Center
Start date: 2016-01-01; Completion date: 2018-06-01
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Over 10% of children in the United States are diagnosed with ADHD, and nearly half of these children have moderate to severe impairments in sleep, further exacerbating their already impaired academic, emotional and social functioning. In children with ADHD, 34% of prescribed sleep medications are antipsychotics that can cause marked weight gain and metabolic changes; alternate medications have either been found to be ineffective, difficult to tolerate or are largely unstudied in youth. Delayed sleep onset is strongly correlated with active symptoms of ADHD and Oppositional Defiant Disorder (ODD), suggesting that better control of disruptive behaviors could improve sleep patterns and this application will assess if the extension of the therapeutic effects of CNS stimulants into the early evening improves sleep onset.

Detailed description:
The goal of this application is to assess the impact of safer treatment option Methylphenidate (MPH) on sleep and behavior problems in children with Attention Deficit Hyperactivity Disorder (ADHD) and Behavioral Insomnia of Childhood (BIC). ADHD affects over 11% of school-aged youth. Similarly, pediatric sleep disorders occur in over a third of children and impact multiple domains of the child's functioning as well as that of their parents. Children with ADHD are at an increased risk for sleep problems with a staggering comorbidity of up to 70%, while sleep deprivation worsens the already impaired social, emotional and academic functioning of children with ADHD. Therefore, improving sleep may translate into enhanced functioning in multiple realms. Delayed sleep onset latency (SOL) and bedtime resistance, the key component of the limit setting type of BIC, are particularly likely to occur in children with ADHD. Medications are commonly used for both conditions with over 6% of all school-aged children in the United States prescribed medication for ADHD and 7% for sleep. In children with ADHD, 34% of prescribed sleep medications are antipsychotics that can cause marked weight gain and metabolic changes. Alternate medications for sleep have either been found to be ineffective, difficult to tolerate or are largely unstudied in youth. MPH has an extensive database supporting their safety and efficacy. Objective sleep studies of MPH have not found consistent results, with a few studies reporting delayed SOL and while others report improved quality of sleep. Therefore, this proposal will evaluate the impact of extending MPH treatment into the early evening on sleep onset using a 3-week with-in subjects randomized trial of .3mg/kg of immediate release (IR) MPH dosed 3 hours before bedtime vs. placebo in 38 children with ADHD and chronically delayed SOL who have a history of prolonged stimulant usage. The investigators will recruit 38 children ages 6-12 of any gender and racial/ethnic status with ADHD who have been treated with stable morning dose of extended release (ER) MPH for an extended time period (30 days or more) from the primary care and psychiatry clinics at Hershey Medical Center in Hershey, PA. Recruitment will be split into three waves (13, 13, 12 participants). Parents will be reminded to administer the blinded medication dose by text message each evening (or phone call by study staff) 3 hours prior to the desired bedtime. Sleep onset will be measured by actigraphy and sleep log, with parents also reporting on level of ODD and ADHD symptoms in the evening.

Arms: arm 1: With-in subjects trial. Subjects will be randomized to 0.3 mg/kg of Immediate Release Methylphenidate versus placebo over 3-weeks duration arm 2: inert placebo ingredient
Interventions: intervention 1: Immediate Release Methylphenidate intervention 2: Placebo
Intervention descriptions: intervention 1: The medication assessment procedure will be a double-blind, within-subject evaluation of placebo and matching evening dose of IR MPH rounded to the nearest 2.5mg increment with a max IR MPH dose of 0.3mg/kg. Expected evening dose range will be from 2.5mg to 20mg with most participants receiving between 5 to 15mg per evening dose. Dose will be determined based on current dose of their morning extended release stimulant intervention 2: inert placebo ingredient

Protocol documents:
Prot_SAP_000.pdf: 
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HRP-592 - Protocol for Human Subject 
Research with Use of Test Article(s)
Protocol Title:
Effects of Evening Dose of Immediate Release CNS Stimulants on Sleep in Children with Attention Deficit 
Hyperactivity Disorder:  A Randomized Placebo-controlled Pilot Study
Principal Investigator:
Name: Raman Baweja, MD, MS
Department: Psychiatry
Telephone: 717-531-8134
E-mail Address: rbaweja@hmc.psu.edu
Version Date: November 17, 2016
Clinicaltrials.gov Registration #:  NCT02638168
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Table of Contents
1.0
Objectives
2.0
Background
3.0
Inclusion and Exclusion Criteria
4.0
Recruitment Methods
5.0
Consent Process and Documentation
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
7.0
Study Design and Procedures
8.0
Subject Numbers and Statistical Plan
9.0
Confidentiality, Privacy and Data Management
10.0
Data and Safety Monitoring Plan
11.0
Risks
12.0
Potential Benefits to Subjects and Others
13.0
Sharing Results with Subjects
14.0
Subject Stipend (Compensation) and/or Travel Reimbursements
15.0
Economic Burden to Subjects
16.0
Resources Available
17.0
Other Approvals
18.0
Multi-Site Research
19.0
Adverse Event Reporting
20.0
Study Monitoring, Auditing and Inspecting
21.0
Future Undetermined Research: Data and Specimen Banking
22.0
References
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1.0
Objectives
1.1
Study Objectives
Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common reasons for child mental 
health referrals in children affecting over 11% of school-aged youth at an annual societal cost of over 40 
billion dollars. Similar to ADHD, pediatric sleep disorders are a significant public health problem as they 
occur in over a third of children and impact multiple domains of the child’s functioning as well as that of 
their parents.  Children with ADHD are at an increased risk for sleep problems with a staggering 
comorbidity of up to 70%, while sleep deprivation worsens the already impaired social, emotional and 
academic functioning of children with ADHD.  Therefore, improving sleep may translate into enhanced 
functioning in multiple realms. Delayed sleep onset latency (SOL) and bedtime resistance, the key 
component of the limit setting type of Behavioral Insomnia of Childhood (BIC), are particularly likely to 
occur in children with ADHD. Oppositional behaviors have been identified as major causes of these sleep 
problems in ADHD youth. Medications are commonly used for both conditions with over 6% of all 
school-aged children in the United States prescribed medication for ADHD and 7% for sleep. In children 
with ADHD, 34% of prescribed sleep medications are antipsychotics that can cause marked weight gain 
and metabolic changes. Alternate medications for sleep have either been found to be ineffective, 
difficult to tolerate or are largely unstudied in youth. 
Methylphenidate (MPH marketed as Ritalin) and Amphetamine (AMPH marketed as Adderall) are 
the two most commonly prescribed CNS stimulant medications for ADHD and they have an 
extensive database supporting their safety and efficacy. While insomnia is a commonly reported side 
effect of this medication class, objective sleep studies of either have not found consistent results, with a 
few studies reporting delayed SOL and while others report improved quality of sleep. For example, one 
study found the switching from BID to TID dosing schedules of immediate release MPH (IR MPH) actually 
led to reductions in SOL by 25%. Past studies have been limited by their setting (inpatient and sleep 
labs), sample (large percentage of treatment naïve patients), design (open label), and assessment 
methods (heavy reliance on parental report). A major limitation has been the failure to disentangle the 
direct effects of MPH and AMPH from that of the exacerbation of ADHD symptoms due to the waning 
of the therapeutic effects of a morning dose of a CNS stimulant (medication rebound). Unfortunately, 
this process occurs during the midst of the bedtime routine for many school aged children treated with 
CNS stimulants, which may lead to worsening in SOL due to increased behavioral problems as children 
are supposed to be calming down for bedtime.  Hence, there is a clear need for alternate treatments 
option for frequently occurring sleep problems in school-aged children with ADHD.
We propose to address the aforementioned limitations through objective measures by using a double 
blind with-in subjects design.  We also propose to evaluate the impact of extending CNS stimulant 
treatment into the early evening on sleep onset in school-aged youth, who have been diagnosed with 
ADHD and currently use MPH or AMPH, to determine if the extension of MPH or AMPH is effective in 
eliminating or lessening interruptions during the bedtime routine.  In addition, this proposal will gather 
the essential preliminary data needed to support a K23 application on multimodal interventions for 
sleep problems in children with ADHD as our center is also developing a novel behavioral treatment that 
targets both sleep hygiene and externalizing behavior symptoms. Our objectives for this study are to:
Aim: In 38 children already stabilized on a regimen of AMPH or MPH who have chronically 
delayed sleep onset latency, we propose to assess the impact of extending CNS stimulant 
treatment into the evening on sleep during a 3-week, with-in subjects randomized trial. Participants 
stable on MPH will be given a 0.3mg/kg dose of IR MPH or placebo between administered in 
the early evening. Those already taking a stable dose of AMPH will be given a 0.15mg/kg dose 
of IR AMPH or placebo in the later afternoon.  
H1: We expect that the Immediate Release CNS stimulants (IR MPH or IR AMPH)  will produce a 
significant reduction in evening levels of ADHD/ODD symptoms compared to placebo, 
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H2: Sleep latency will be significantly shorter on days with IR MPH/AMPH vs placebo
H3: Improvement in evening symptoms of ADHD/ODD will be correlated with change in sleep latency.
1.2
Primary Study Endpoints
The primary outcome in this study will be the duration of time in bed until sleep measured in minutes 
(Sleep onset latency; SOL) as reported on the parent completed sleep log. Sleep logs are the most 
reliable means for assessing SOL. 6, 13, 31 Parents will complete the paper sleep log every 15 minutes 
starting with the first request to go to bed until the child is asleep for two intervals.
1.3
Secondary Study Endpoints
Sleep onset latency (SOL), defined as time in bed until sleep, will be measured by sleep log vs. actigraphy 
as sleep logs are commonly used in ADHD sleep studies and because SOL is the least reliable sleep 
parameter on actigraphy.6,13,31 Parents will complete the paper sleep log every 15 minutes starting with 
the first request to go to bed until the child is asleep for two intervals, and record the time first in bed. 
In the morning, they will record nighttime wakings, morning wake time and the time the child arises 
from bed to calculate total time in bed. As recommended, actigraphy and sleep logs will both be used to 
enhance data quality and obtain objective and subjective markers of habitual sleep patterns.32 
Participants will wear the GT3X ActiGraph (Pensacola, FL) on their non-dominant hand for two weeks at 
baseline, during study period (3 weeks) from 30 minutes before bedtime to 30 minutes after morning 
rising, set at 30Hz using 1 minute epochs. Besides sleep onset and SOL, actigraphy will measure sleep 
offset, total sleep time, wake after sleep onset (WASO), sleep efficiency, number and length of wakings 
and night to night variability (weekends & weekdays).  The parent rated 10-item IOWA Conners will 
assess change in ADHD and ODD symptoms specifically during the time periods between 6pm to bed 
time.33 The parents rated 7-item the Affective Reactivity Index (ARI) will assess change in irritability.42 All 
scales have been found to be reliable markers of treatment response.25 We will use the Pittsburgh Side 
Effects Rating Scale (PSERS) to evaluate adverse reactions to MPH and AMPH.34 The PSERS lists common 
stimulant induced adverse events rated none too severe. It was used in the MTA and other stimulant 
trials.35,36 As side effects and ADHD/ODD symptoms will be completed nightly during these 3 weeks of 
treatment, we elected to use these brief measures. These brief measures have been found to be as 
sensitive for detecting treatment effects of CNS stimulants compared to lengthier measures that assess 
the entire range of DSM externalizing symptoms.25
2.0
Background
2.1
Scientific Background and Gaps
Children with ADHD have more sleep disturbances than those without ADHD, irrespective of their 
medication status.1 Behavioral Insomnia of Childhood (BIC) is the most common sleep disorder seen in 
youth with ADHD with delayed sleep onset latency (SOL) being the primary manifestation of BIC.2 Rates 
of BIC exceed in children with ADHD those seen in children with mood and anxiety disorders.3 
Contributing factors to a prolonged SOL in children with ADHD include poorly structured night time 
routines, highly variable bedtimes and elevated levels of bedtime resistance.4,5  Sleep deprivation has 
been also linked with oppositional  behavior and irritability6,43. Sleep experts have concluded that 
oppositional behaviors likely drive the majority of sleep problems in children with ADHD, suggesting that 
helping parents to manage these behaviors may improve the child’s sleep.6,7  
Behavioral interventions for sleep problems may be more difficult to implement in youth with ADHD and 
there is very little data on the behavioral treatment of sleep in youth with ADHD.2 Not surprisingly, 
medications are the most common intervention for sleep problems in youth with ADHD. Most 
medications for sleep have been found to be ineffective, or are largely unstudied in youth.8 In children 
with ADHD, 34% of prescribed sleep medications are antipsychotics.1  However, the use of antipsychotic 
medication in ADHD youth without serious psychiatric comorbidity is difficult to recommend given the 
concerning side effect profiles of these medications,9 their limited efficacy for ADHD10,11 and increased 
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concerns over polypharmacy in children.12 Melatonin has been proven efficacious under controlled 
settings but does not impact ADHD symptoms and most responders still exhibit prolonger sleep 
latencies.13 Hence, there is a clear need for additional treatments options.
2.2
Previous Data
N/A
2.3
Study Rationale
CNS stimulant medications have an extensive database supporting their safety and efficacy in children, 
but there is a strong perception among parents and clinicians that stimulant can worsen sleep problems 
based on their wakefulness promoting properties.14 Objective sleep studies measuring effects of MPH 
have not found consistent results. Stimulant regimens designed to control symptoms during the school 
lose efficacy as bedtime approaches, leading to worsening behavior in the early evening.15 Rebound 
ADHD symptoms when children are trying to settle for bedtime have been theorized to prolong 
SOL.7,16,17 Therefore, extending the effects of CNS stimulants may lead to improved SOL through 
reduction of disruptive behaviors in the evening. 
In treatment naive youth, afternoon doses of IR MPH worsen SOL.18 However, many side effects of CNS 
stimulants fade over time.19 Therefore, results in treatment naïve youth may not translate to chronically 
treated youth. In fact, later day dosing of CNS stimulants has been found to improve sleep in children 
and adults with ADHD.16 Stein et al. found that SOL was reduced by 25% when the therapeutic effects of 
CNS stimulants were extended into the early evening by a adding a third dose of IR MPH in a double 
blind controlled trial in children already optimized on a IR MPH regimen.20 The last dose in the TID 
regimen was at 4pm which may not have prevented a symptom exacerbation during the bedtime 
routine for some participants, possibly blunting observed the improvements in SOL. Extending the wear 
time of the MPH patch in children from 9 to 12 hours exerted a tendency toward improved sleep quality 
on subjective measures21, while MPH dosed as late as 8pm led to reductions in the frequency of night-
time awakenings leading to improved sleep quality in adults.22 Likewise, one study in children chronically 
treated with CNS stimulants found that dosing extended release amphetamine products so they carry 
into the evening resulted in a higher sleep efficiency compared to placebo, although did not reach to 
statistical significance.46  
The impact of extending CNS stimulant effects into the evening on SOL has not been adequately 
investigated and merits further study in light of the limitations of current practices for improving sleep 
in children with ADHD.
3.0
Inclusion and Exclusion Criteria
3.1
Inclusion Criteria
1. Ages 6-12 (inclusive), as sleep architecture changes as children pass through puberty.23
2. Children who have been treated with a stable morning dose of Extended Release Methylphenidate or 
Amphetamine (ER AMPH)  or twice daily dose of Immediate Release Methylphenidate or immediate 
release amphetamine (IR AMPH)  for an extended period of time (30 days or longer).
3. DSM V diagnosis of Attention Deficit Hyperactivity Disorder (ADHD): Diagnosis will be assessed on the 
NIMH Computerized Diagnostic Interview Schedule for Children (C-DISC)24, and parent and teacher 
rating scales.25  The C-DISC is a structured parent interview that is widely used in pediatric mental 
studies to classify diagnostic status.  Computerized administration is over seen by trained study staff and 
the computerized diagnostic score is overseen by MD/PhD level faculty.  Assessment questions for the 
C-DISC are not provided with this IRB submission as questions vary depending on subject responses, and 
a file containing the questions would be too large (100+ pages).  Additionally, as evening levels of ADHD 
and Oppositional Defiance Disorder (ODD) symptoms are theorized to mediate improvements in sleep 
onset latency (SOL), scores at or above the 90th percentile on the 10 item IOWA Conners, specifically 
during the time period between 6:00 p.m. to bed time will be required. This cutoff represents an 
elevated level of disruptive symptoms for the age.26  
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4. Children with any ADHD subtype meeting the above criteria will be eligible, although, it is expected 
that the majority will be of the Combined subtype of ADHD given the associate between this subtype 
and ODD smtpoms.27  A diagnosis of any of the two Behavioral Insomnia of Childhood (BIC) subtypes 
associated with delayed SOL (limit setting or combined type) will be required.28 A SOL ≥30  minutes for 
the past three months by parent report and verified during a 14 day pre-baseline assessment (parent 
completed sleep log) will be required. In a large population-base study, average sleep onset latency was 
17.2 minutes in school age children.49 Additionally, widely used sleep screening instrument ‘Children’s 
sleep Habits questionnaire’ in school-aged children – indicates that normal sleep onset latency should 
be less than 20 min.50 Therefore, we feel that lowering the SOL threshold will allow more children in 
need of treatment to enroll without inadvertently including those with minimal impairing sleep 
problems. In children, SOL is typically ≤ 20 minutes with a SD of 15 minutes.30  Further, the delayed SOL 
must persist once stimulant medication is stopped, which will be verified through the 14 day parent 
completed sleep log, with children stopping their stimulant medication on 2 of the 14 days. The 
unmedicated assessment days are included to document that the delayed SOL does not resolve with 
stoppage of the CNS stimulant.   Susan Calhoun, PhD, will confirm the diagnosis of BIC through review of 
parent completed sleep log and parent completed sleep assessment.  Dr. Calhoun has over a decade of 
experience in the assessment and behavior management of pediatric sleep disorders.  
4. Sex:  male or female
5. Fluent in written and spoken English.
6. Children who can swallow capsules. 
3.2
Exclusion Criteria
1. Age <6 years of age or >12 years of age.
2. Children who have not had Methylphenidate or Amphetamine (Extended Release or Immediate 
Release) treatment for an extended period of time (30 days or longer).
3. A diagnosis or suspicion of sleep-disordered breathing will be exclusionary as it is not expected to be 
impacted by Immediate Release Methylphenidate treatment.
4. Current psychotropics other than CNS Stimulants (Extended Release or Immediate Release 
Methylphenidate or Amphetamine). Children prescribed alpha agonists for adjunctive control of ADHD 
in combination with a MPH product will be allowed to enroll as long as they meet all other entry criteria 
(i.e. sleep must remained impaired with use of alpha agonist). 
5. Regular use of other medications that impact sleep within the last 14 days (i.e.: sedating 
antihistamines, melatonin).
6. Active medical/psychiatric conditions that impact sleep (i.e.: severe asthma, Autism Spectrum 
Disorder diagnosis, marked developmental delay, or mood/anxiety disorder).
3.3
Early Withdrawal of Subjects
3.3.1
Criteria for removal from study
Participants are free to withdraw at any time from the study.  The principal investigator may 
withdraw participants from the study at any time without patient consent for health and safety 
reasons, failure to adhere to protocol requirements, participant consent withdrawal, or if it is in 
the participant’s best interest.  Any participant experiencing a 50% worsening in sleep onset 
latency will be discontinued, and participants can be brought in for additional visits as needed to 
asses tolerability or efficacy concerns.
3.3.2
Follow-up for withdrawn subjects
If participants withdraw or are withdrawn from the study prior to the completion of the study, 
they will not be replaced.  Research staff will contact the participants for close up visit for 
assessment of safety, to collect and obtain any possible data that may be available such as 
partial sleep logs and/or actigraphy data.). 
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4.0
Recruitment Methods
4.1
Identification of subjects
Potential research participants will be recruited through mailed flyers, flyers provided within pediatric 
and psychiatric clinics within Hershey Medical Center, and Penn State Children’s Hospital website. 
CareLine staff will also be provided with language in order to provide interested research participants 
with information about the study (supporting form included in this IRB modification submittal).  
CareLine will forward all interested participant information to research staff.  An on-hold message 
through Penn State Hershey Medical Center will also be used to recruit participants.
4.2
Recruitment process
Participants will be recruited from pediatric and psychiatric clinics at Penn State Hershey Medical 
Center, as well as through mailed flyers. Recruitment efforts will also take place through the Penn State 
Children’s Hospital website, where a link and description of the study will be included, Penn State Milton 
S. Hershey Medical Center Facebook page, and the Penn State Hershey Research Facebook page to 
display the IRB approved recruitment flyer.  Interested parents will be instructed to call research staff to 
complete a brief screening for eligibility over the phone.  Participants meeting the phone screen criteria 
will be invited to schedule an intake appointment at the Hershey Medical Center Psychiatry Clinic at 22 
Northeast Drive.
4.3
Recruitment materials
See documents attached in CATS:

recruitment flyer

cover letter to mail with ABC Brochure and recruitment flyer

text for CareLine document

text for on-hold message document.

text for Penn State Children’s Hospital website document
4.4
Eligibility/screening of subjects
See attached phone screening form.
5.0
Consent Process and Documentation
5.1
Consent Process 
 
5.1.1
Obtaining Informed Consent
5.1.1.1
Timing and Location of Consent
Consent procedures will take place at the 22 Northeast Drive, HMC Department 
of Psychiatry Child Research Annex and will be conducted by the principal 
investigator or other MD/PhD level study staff approved to collect consent.  The 
consent visit will be scheduled after meeting screening criteria from the phone 
screen.
5.1.1.2
Coercion or Undue Influence during Consent
The potential participant and parent will be told that the research is voluntary.  
The potential participant and parent will be told that the research will not 
impact their treatment at all, and that he or she may refuse research at any 
time.
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5.1.2
Waiver or alteration of the informed consent requirement
N/A
5.2
Consent Documentation
5.2.1
Written Documentation of Consent
No research will be conducted until after consent has been obtained.  After a potential 
participant is identified via the phone screen with the participant’s guardian, the participant and 
guardian will be approached by a member of the research staff to discuss the consent process.  
The member of the research staff will inform the parent and child about the purpose of the 
study, the risks and benefits, and the procedures for the study.  During this conversation, the 
member of the research staff will assess the level of insight of the parent/guardian of the 
patient into the illness.  If the parent is unable to demonstrate adequate insight, the member of 
the research staff will decide that they are unable to consent at that time.  If the parent is 
interested and eligible they will sign the consent form. Parents will be offered the opportunity to 
take the consent home for further review before signing, in which case the intake process will 
end for that day.  A copy of the signed consent form will be provided to the family.
5.2.2
Waiver of Documentation of Consent (Implied consent, Verbal consent, etc.)
Verbal consent is required to complete the phone screen.  PHI will be collected to determine if a 
potential subject has any cardiovascular conditions or a family history of cardiovascular 
conditions to determine study eligibility. 
5.3
Consent – Other Considerations 
5.3.1
Non-English Speaking Subjects
N/A
5.3.2
Cognitively Impaired Adults
N/A
5.3.2.1 Capability of Providing Consent
N/A
5.3.2.2
Adults Unable To Consent
N/A
5.3.2.3 Assent of Adults Unable to Consent
N/A
5.3.3
Subjects who are not yet adults (infants, children, teenagers) 
5.3.3.1 Parental Permission
Designated members of the research team will meet with the parent or legal 
guardian to review the consent document in a private area and then answer all 
questions regarding to the study.  Consent will be provided via a signature area 
labeled “Signature of Parent(s)/Guardian for Child”.  Legal guardians will be 
requested to provide documentation of their guardianship.
5.3.3.2 Assent of subjects who are not yet adults
All participating children will be between 6 and 12 years of age.  Study doctors will 
review the study with the potential participant as well as their legal guardian in a 
private area.  Once the assenting clinician has verified that the child has an age 
appropriate understanding of the study and is willing to participate, the child will 
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then sign the consent form under the section assent for research participant ages 7 
and up.  Due to their level of cognitive maturity or severity of behavioral symptoms 
(as this study targets child with attention and/or oppositional behaviors), some 
children may not be able to express sufficient understanding of the study.  In such 
cases, the assenting clinician will verify with the parent that the child will be a 
willing and appropriate participant but that their behavioral symptoms prevent 
them from signing assent.  In such cases, the need for child signature will be 
waived and the consenting clinician will document the reason the child’s signature 
was not obtained.
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
6.1
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
Check all that apply:
 
Not applicable, no identifiable protected health information (PHI) is accessed, used or 
disclosed in this study. [Mark all parts of sections 6.2 and 6.3 as not applicable]
Authorization will be obtained and documented as part of the consent process. [If this is the 
only box checked, mark sections 6.2 and 6.3 as not applicable]
Partial waiver is requested for recruitment purposes only (Check this box if patients’ medical 
records will be accessed to determine eligibility before consent/authorization has been 
obtained). [Complete all parts of sections 6.2 and 6.3]
Full waiver is requested for entire research study (e.g., medical record review studies). 
[Complete all parts of sections 6.2 and 6.3]
Alteration is requested to waive requirement for written documentation of authorization 
(verbal authorization will be obtained). [Complete all parts of sections 6.2 and 6.3]
6.2
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
6.2.1
Access, use or disclosure of PHI representing no more than a minimal risk to the privacy of the 
individual
6.2.1.1 Plan to protect PHI from improper use or disclosure
Each participant will be assigned a unique study ID code.  The only identifying 
information on any study form will be that ID code.  PHI will not be recorded on 
any study assessment form other than the phone screen and consent form.  These 
two forms will be kept in separate locked file apart from the rest of the study data 
for individual participants.  The only database linking study ID number to PHI will 
be stored on a secure departmental server accessible only to core study staff.
6.2.1.2 Plan to destroy identifiers or a justification for retaining identifiers 
No PHI will be encoded on study forms.  Participants’ phone screens that contain 
PHI will be kept in a secure locked area within the research site to ensure that we 
have a means to contact families if needed.
6.2.2
Explanation for why the research could not practicably be conducted without access to and 
use of PHI
This is a study of the effects of Immediate Release Methylphenidate on ADHD in children, which 
requires examination of individual participants.
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6.2.3
Explanation for why the research could not practicably be conducted without the waiver or 
alteration of authorization
PHI will be collected over the phone via phone screen.  This requires a waiver of authorization 
statements of agreement because it is necessary to determine that a potential child subject 
does not have any cardiovascular or other medical or psychiatric conditions, which would deem 
them as ineligible. The phone screen will also verify that the child has been on a stable dose of 
an eligible ADHD medication for the required time. By collecting this information in advance, we 
can minimize burden to families by identifying those who are clearly ineligible prior to the 
lengthy consent and assessment visit.
6.3
Waiver or alteration of authorization statements of agreement
PHI will be collected over the phone via phone screen.  This requires a waiver of authorization 
statements of agreement because it is necessary to determine that a potential child subject does not 
have any cardiovascular conditions or a family history of cardiovascular conditions, which would deem 
them as ineligible.
7.0
Study Design and Procedures
7.1
Study Design
This is a double blind with-in subjects designed trial.  The initial visit will be for consent and eligibility 
determination (Visit 1).  Our core intervention will consist of 3-week with-in subjects randomized trial of 
adding a 0.3mg/kg of Immediate Release (IR) Methylphenidate (MPH) dosed 3 hours before bedtime vs. 
placebo (Visits 2-4).  
7.2
Study Procedures
7.2.1
Visit 1 (Intake, 2 weeks):
Participation will involve an approximately two hour intake appointment where the participating 
child and legal guardian will be introduced to the study, and be consented and assented.  The 
legal guardian will complete a standard set of clinical diagnostic interviews to assess pediatric 
psychopathology, as well as rating scales of the child’s behavior and sleep habits. Parents will 
be also provided rating scales for child’s teacher to complete and a record 
release form to obtain teacher data.  Participant vitals (height, weight, blood pressure, 
and pulse) will be obtained. After the intake appointment, parents will be provided with a brief 
sleep log to record this child’s time in bed, time to sleep, as well as wake time for the next 14 
days.  For two of these 14 days, it will be required that the child not take their normal morning 
dose of extended release of methylphenidate or amphetamine to ensure that the delayed sleep 
onset is not caused by the methylphenidate/amphetamine.  Parents will select which two days 
are best suited for the child to minimize the impact of a potential increase in ADHD symptoms. 
SOL (time in bed until sleep onset) will be measured by sleep log vs. actigraphy as sleep logs are 
commonly used in ADHD sleep studies and because SOL is the least reliable sleep parameter on 
actigraphy.6,13,31 Parents will complete the paper sleep log every 15 minutes starting with the 
first request to go to bed until the child is asleep for two intervals, and record the time first in 
bed. In the morning, they will record nighttime wakings, morning wake time and the time the 
child arises from bed to calculate total time in bed. As recommended, actigraphy and sleep logs 
will both be used to enhance data quality and obtain objective and subjective markers of 
habitual sleep patterns.32 Participants will wear the GT3X ActiGraph (Pensacola, FL) on their non-
dominant hand for two weeks at intake, during study period (3 weeks) from 30 minutes before 
bedtime to 30 minutes after morning rising, set at 30Hz using 1 minute epochs. Besides sleep 
onset and SOL, actigraphy will measure sleep offset, total sleep time, wake after sleep onset 
(WASO), sleep efficiency, number and length of wakings and night to night variability (weekends 
& weekdays).  These parameters will be used to assess eligibility for the study, as we only want 
to enroll children who have a current and persistent delay in SOL.  It should take parents 5 
minutes or less to complete the sleep log each day.  Sleep logs will be reviewed by Susan 
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Calhoun, PhD, who has over a decade of experience in the assessment and behavioral treatment 
of pediatric sleep disorders.  She will also assess for the presence of any exclusionary sleep 
disorders using the parent completed Pediatric Sleep Questionnaire.29 Participants will not be 
enrolled until after Dr. Calhoun has confirmed the presence of SOL on the 14 day intake sleep 
log.  The C-DISC will be used to confirm the presence of a DSM IV disruptive behavioral disorder 
(DBD), assess psychiatric comorbidity with diagnoses confirmed by an MD/PhD prior to decisions 
on eligibility.  Subthreshold mood and anxiety symptoms will be assessed as a covariate vs. 
being exclusionary as they are commonly seen in youth with BIC.
Sleep logs will be reviewed by phone prior to scheduling visit 2 to determine eligibility. Once all 
data to determine eligibility are collected, eligibility will be determined and parents of eligible 
participants will be asked to participate in the three weeks of IR MPH treatment.
7.2.2
Visit 2 (Baseline):
The screening sleep log will be reviewed to confirm persistently delayed SOL on or off ADHD 
medication. Participants will be evaluated by study physicians.  Participants who are already 
taking a stable dose of MPH will be treated with blinded IR MPH (max dose 0.3mg/kg up to a 
maximum of 20mg)) and placebo dosed between 3 to 3.5 hours prior to bedtime over a three 
week period with dose (identified IR MPH dose or placebo) randomly assigned for each day.  As 
the therapeutic effect of IR MPH lasts at least 4 hours,38 and that for IR AMPH at least four 
hours47 this dosing time should ensure that ADHD/ODD symptoms are not increasing in the 
midst of the bedtime routine. All children will continue on their current morning dose of an 
Extended Release (ER) Methylphenidate (MPH).  For children whose current daytime MPH 
regimen is less than equivalent of 0.3mg/kg/day of IR MPH, their evening dose will be matched 
to their daytime dose rounded to the nearest 2.5mg increment (e.g., Concerta 18mg = IR MPH 
5mg TID). No participant will receive an evening dose higher than 0.3mg/kg. For children stable 
on a IR or ER AMPH regimen, they will be treated with blinded IR AMPH (0.15mg/kg up to a 
maximum dose of 10mg) and placebo dosed 4.5 to 5 hours prior to bedtime over a three-week 
period with dose alternating daily given the greater therapeutic duration and potency of IR 
AMPH vs MPH45, 48 AMPH has a longer therapeutic half-life and is twice as potent as MPH which 
is why the timing and mg/kg/dose is adjusted48. Participants will continue on their current dose 
of morning ER AMPH. For children whose current daily dose is less than 0.15mg/kg/day of IR 
AMPH, their evening dose will be matched to their current daytime dose (e.g. Adderall XR 10mg 
or Vyvanse 30mg = IR AMPH 5mg). The maximum dose of IR AMPH given will be 10mg.
A 21 day supply of blinded medication/matching placebo will be dispensed at the visit in weekly 
pill reminders with each day labeled.  To help ensure reliable dosing, parents will have the 
option of daily dosing reminder by text message from study staff. Similar proceeds have been 
used in studies of chronic medical disease in children and found to improve administration of 
medication at the optimal time.39 Text messages will be generated and scheduled to send to the 
child’s parent’s cell phone at a set time through Microsoft Outlook on the HMC server from a 
study staff’s HMC email.  The set time will be 3 to 3.5 hours prior to the child’s bedtime as 
determined by the child’s parent(s).  The reminder message will read as follows: “This is a 
reminder to administer your child’s study medication at X:XX p.m. today”. A delivery receipt will 
be requested in the generation of the email to ensure deliverance of the text.  Study staff will 
regularly check email to ensure the delivery occurred.  Regular text message rates and charges 
will apply as per the family’s mobile phone plan.  Families will not be reimbursed for any 
incurred costs related to the reminder text messages.  To verify time of dosing, parents will be 
asked to record time when they will give the evening dose of MPH/AMPH /placebo rounded to 
the nearest 5 min interval on the sleep log.  Parents will complete the IOWA Conners ADHD 
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Rating Scale, Sleep Logs, the Affective Reactivity Index, Inattention Rating Scale, and the 
Pittsburgh Side Effects Rating Scale (PSERS).  The parent rated 10 item IOWA Conners will assess 
change in ADHD and ODD symptoms specifically during the time periods between 6:00 p.m. to 
bed time.33 The parents rated 7-item the Affective Reactivity Index will assess change in 
irritability44. All scales have been found to be reliable markers of treatment response.25 We will 
use the Pittsburgh Side Effects Rating Scale (PSERS) to evaluate adverse reactions to 
MPH/AMPH.3  If necessary, participants vitals will be obtained. For example, if vitals were not 
collected at visit 1, or if a significant amount of time has lapsed between visit 1 and 2 (four 
weeks or more).  Participants will continue to wear the GT3X ActiGraph (Pensacola, FL) on their 
non-dominant hand from 30 minutes before bedtime to 30 minutes after morning rising, set at 
30Hz using 1 minute epochs. Sleep log and actigraphy data will be collected.
7.2.3
Visit 3 (3-14 days after administration of medication):
Participant vitals will be obtained and participants will be evaluated by study physicians.  Study 
physicians will ensure that the participant’s SOL is not markedly worsened by study medication 
by reviewing the parent reported sleep log.  Any child experiencing a 50% worsening in SOL will 
be either prescribed a lower dose of MPH/AMPH (decrease by at least a 2.5mg increment) or 
discontinued. Dose may be lowered to address other side effect concerns. Participants will 
continue to be treated with blinded IR MPH/AMPH (at the same dose dispensed at visit 2 unless 
there is a side effect concern) and placebo dosed 3 to 3.5 hours prior to bedtime.   All children 
will continue on their pre-study morning dose of an Extended Release (ER) Methylphenidate 
(MPH) or Amphetamine (AMPH).  To verify time of dosing, parents will be asked to record 
time when they will give the evening dose of MPH/placebo rounded to the nearest 5 min 
interval on the sleep log.  Parents will complete the IOWA Conners ADHD Rating Scale, Sleep 
Logs, the Affective Reactivity Index, Inattention Rating Scale, and the Pittsburgh Side Effects 
Rating Scale (PSERS).  Participants will continue to wear the GT3X ActiGraph (Pensacola, FL) on 
their non-dominant hand from 30 minutes before bedtime to 30 minutes after morning rising, 
set at 30Hz using 1 minute epochs. Sleep log data will be collected.
7.2.4
Visit 4 (Endpoint): 
Participant vitals will be obtained and participants will be evaluated by study physicians. Parents 
will complete the IOWA Conners ADHD Rating Scale, Sleep Logs, the Affective Reactivity Index, 
Inattention Rating Scale, and the Pittsburgh Side Effects Rating Scale (PSERS). Sleep log and 
actigraphy data will be collected.  GT3X ActiGraph (Pensacola, FL) will also be collected.  IR MPH 
vs. placebo will not be administered.  No treatment will be applied at this visit.  
7.3
Duration of Participation
Participation in the study will last approximately five to seven weeks, which includes the 2 week intake 
assessment and 3 study visits.
7.4
Test Article(s) (Study Drug(s) and/or Study Device(s))
7.4.1
Description
This primary aim of this study is to evaluate if variations in dosing patterns lead to better 
symptom control for ADHD that impacts evening behavior. The medication used in this study 
will be IR MPH/AMPH which is FDA approved for the treatment of pediatric ADHD and the most 
extensively studied ADHD medication in children.45 All study drug will be used only for FDA 
approved purposes (to treat ADHD in children ages 6 to 12) without modification to its approved 
packaging. It will be administered in its unaltered commercially available form and dosed in 
accordance with the guidelines outlined in its respective FDA approved packaging. Therefore, 
according to FDA policy 21 CFR312.2b1, we do not believe that the study requires an IND. 
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7.4.2
Treatment Regimen
The medication assessment procedure was a double-blind, within-subject evaluation of placebo 
and matching evening dose of IR MPH/AMPH rounded to the nearest 2.5mg increment with a 
max IR MPH dose of 0.3mg/kg and a max IR AMPH dose of 0.15mg/kg. Expected evening dose 
range will be from 2.5mg to 20mg with most participants receiving between 5 to 15mg per 
evening dose. Dose will be determined based on current dose of their morning extended release 
stimulant. Equivalent dose of ER-MPH is double of ER Dex-MPH. 
Participants will continue on their current dose of morning ER AMPH. For children whose 
current daily dose is less than 0.15mg/kg/day of IR AMPH, their evening dose will be 
matched to their daytime dose (e.g. Adderall XR 10mg or Vyvanse 30mg = IR AMPH 
5mg). The maximum dose of IR AMPH given will be 10mg.
AM ER MPH dose 
for OROS MPH
AM dose of ER 
non OROS 
MPH
AM dose ER 
Dex-MPH
Matching IR 
MPH dose
18mg
10mg
5mg
5mg
27mg
NA
7.5mg
36mg
20mg
10mg
10mg
54mg
30mg
15mg
15mg
72mg or more
40mg or more
20mg or more
20mg
*max IR MPH dose of 0.3mg/kg, max dose is 20mg
AM ER Adderall 
XR 
AM dose of 
Vyvanse 
Matching IR 
AMPH  dose
5mg
20mg
2.5mg
10mg
30mg
5mg
15mg
40mg
7.5mg
20mg
50mg
10mg
25mg 
60mg 
10mg
30mg or more
70mg or more
10mg
*max IR AMPH dose of 0.15mg/kg or 10mg 
Caregivers who have consented to the study will administer the encapsulated drug product to 
their children (subjects) 3 to 3.5 hours (IR MPH or placebo) before bedtime and 4.5 to 5 hours 
(IR AMPH or placebo) prior to bedtime over a three week period.  Text message reminders will 
be sent to caregivers if they wish to receive such reminders.  Dose will not be increased during 
the trial but can be lowered if intolerable side effects are reported in increments of 2.5mg. 
Participants who cannot tolerate an efficacious dose will be discontinued. Blinded medication 
will be dispensed in containers created by IDS with each daily dose labeled. All participants will 
only need to take 1 dose a day. Families will be provided with written dosing instructions.
7.4.3
Method for Assigning Subject to Treatment Groups
The whole period of active study treatment will last three weeks (21 days). For all participants, it 
will start on a Friday and end on the third Thursday. Each subject will receive a random mixture 
of immediate release methylphenidate/amphetamine (IR MPH/AMPH, in a total of 11 days) and 
placebo (total of 10 days).  Each subject will receive IR MPH for 1 day per weekend for each of 
the three weekends.  During the weekday (Sunday to Thursday) subjects will receive at least two 
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evening dose of IR MPH/AMPH per week for a total of 8 days in the three-week period, resulting 
a total of 11days (3 days on weekends and 8 days on weekdays) on IR MPH/AMPH  over the 21 
days of the study. Randomization schedule will be generated by Dr.  Junjia (Jay) Zhu, Ph.D., 
Assistant Professor of Biostatistics at Penn State Hershey Medical Center, and will be directly 
forwarded to Interventional Drug Pharmacy. Individualized dosing schedules will be provided to 
the IDS for each participant. Our group has employed similar procedures for within subject trials 
of CNS stimulants. 37, 40i
Week1
Week2
Week3
Weekend
Weekday
Weekend
Weekday
Weekend
Weekday
 
Fr
Sa
Su
Mo
Tu
We
Th
Fr
Sa
Su
Mo
Tu
We
Th
Fr
Sa
Su
Mo
Tu
We
Th
ID
D1 
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
D14
D15
D16
D17
D18
D19
D20
D21
1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…
37
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
38
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.4.4
Subject Compliance Monitoring
Parents will record that time of the ER MPH/AMPH dosing in the morning as well as the IR 
MPH/AMPH dosing in the evening in the sleep log. Medication adherence will be assessed at 
each study visit by parent report, review of sleep log and by pill count. 
7.4.5
Blinding of the Test Article
IR MPH/AMPH will be blinded using opaque pill capsules with methylcellulose used as the inert 
placebo ingredient, packaged in matching capsules.  All prescribed doses can be fit into one 
capsule so no participant will need to take more than one capsule a day. All research staff and 
participants will be blinded to medication assignment. Research staff will be able to access the 
list outside of pharmacy hours emergently if needed.
7.4.6
Receiving, Storage, Dispensing and Return 
7.4.6.1
Receipt of Test Article 
The IDS will order, receive, prepare all medication, medication packaging and 
labels. The IR MPH/AMPHTablets and placebo will be encapsulated in identical 
opaque capsules filled with methylcellulose. 
7.4.6.2
Storage
With the exception of already dispensed medication, all medication will be 
stored at the IDS.  Study staff will transport medication from the IDS to the 
research site at 22 NE Drive when needed for participant visits.  Study staff will 
track medication received from the IDS, dispensed to the participant, received 
back from the participant and then returned to the IDS. All medication onsite at 
22 NE Drive will be stored in a locked medication room designed specifically to 
hold controlled substance medication. It has keypad entry and double locked 
cabinets. With the exception of already dispensed medication, all medication 
will be stored at the IDS.  In the event of overnight drug storage, a daily count of 
medication will be documented by a study physician.  Documentation will be 
provided to IDS weekly.  Temperature at the NE Drive medication room will be 
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logged daily. Temperature record logs will be documented daily and 
documentation will be provided to IDS weekly.  Alternatively, participating 
families may come to the UPC Cancer pharmacy to receive study medication as 
has been done in other protocols based at HMC. At the dispensing visit, study 
physicians will verify the participant name on the label matches the name of the 
child attending the visit. In the study medication database, the ID of the 
dispensing clinician, the name, dose and amount of the medication as well as 
the data and subject ID will be recorded. In addition, the amount of prior 
medication returned by families as well as the amount of medication returned 
to the IDS will be recorded at each visit. 
7.4.6.3
Preparation and Dispensing
Medication assignment (IR MPH/AMPH dose or placebo) will be randomly 
assigned per day for the 21 day dosing period.  A computer generated 
randomized medication schedule for the 21 days of treatment will be provided 
to the Investigational Drug Service (IDS) pharmacy following procedures 
employed by our research group in past trials of CNS stimulants37 40.  The IDS will 
prepare all study medication. IR-AMPH does not come in the dosage required 
for the study. IR-AMPH has score line and the tablet will be split evenly on the 
score lines using a pill-splitter, each half will have around IR-AMPH 2.5 mg. IDS 
pharmacy can visually identify a split between 1.5 mg to 4 mg with confidence.   
Any split outside of this range of IR-AMPH tablet will be discarded.   In the 
previous trials, dose range of IR-AMPH is between 5-30mg with dose difference 
range is 5-10mg (Pelham et al, 2001, Regina et al, 2001, Spencer et al, 
2006). There is typically no significant difference between doses 5mg apart 
suggesting that the variance caused by splitting pills will not have a meaningful 
effect on efficacy or tolerability. For example, in Pelham et al, 2001, meaningful 
dose differences required a 10mg difference whereas pill splitting should 
only cause a variance of 1mg or so. Moreover, the slight increase or decrease in 
milligrams of the dose remains well within the therapeutic window of approved 
does of amphetamine (max single dose strength is 30mg). 
  IR MPH/AMPH will be blinded using opaque pill capsules with methylcellulose 
used as the inert placebo ingredient, packaged in matching capsules. Study staff 
will transport medication from the IDS to the research site at 22 NE Drive when 
needed for participant visits.  Study staff will track medication received from the 
IDS, dispensed to the participant, received back from the participant and then 
returned to the IDS.
7.4.6.4
Return or Destruction of the Test Article
Study staff will track medication receive from the IDS, dispensed to the 
participant, received back from the participant and then returned to the IDS.  
IDS will dispose of returned or unused study medication in accordance with 
institutional policies as well as state and federal laws. 
7.4.6.5
 Prior and Concomitant Therapy
Concomitant medicines that are permitted include Extended Release 
Methylphenidate/Amphetamine or twice a day Immediate Release 
Methylphenidate/Amphetamine, as this is required for study eligibility.  Alpha 
agonists prescribe for adjunctive control of ADHD in combination with an MPH 
product will be allowed as the combination is FDA approved.  Current 
psychotropics other than Methylphenidate/Amphetamine (extended Release or 
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Immediate Release Methylphenidate/Amphetamine), and regular use of other 
medications that impact sleep (i.e.: sedating antihistamines, melatonin) are not 
permitted during the study.  Information regarding prior and/or concomitant 
medical therapy will be collected via phone screen by study staff, and 
monitored study physicians at each visit. Participants will be allowed to 
continue with any existing behavioral therapies (e.g. counseling) and will not be 
restricted from accessing any medical treatments during the course of the study 
except for those specifically designed to reduce sleep onset latency. 
8.0
Subject Numbers and Statistical Plan
8.1
Number of Subjects
The total number of subjects to be accrued is 38.
8.2
Sample size determination
Sample size was determined using Optimal Design software (version 3.01) for a person-randomized 
repeated measures design with the following assumptions:  alpha = .05; power (1-beta) = .80; 
observations per condition = 7; standardized treatment effect = .50; between treatment variability = 1.0; 
within-person (repeated measures) variability = 0.25. The assumption of four times greater variability 
between-treatments versus within-person is reasonable given past research. Likewise, the treatment 
effect is supported by prior work that has observed a reduction of SOL by 25% with a late afternoon 
dose of a IR CNS stimulant, producing an estimated effect size of .5 based on the typical variance in 
SOL in ADHD youth.20,30 Taking these assumptions, a power by sample size graph suggests a sample size 
of 35 participants to achieve statistical power of .78. Based on these calculations and reported attrition 
rate in previous stimulants studies of approximately 10% ,20,22 an N of 38 subjects is determined to be 
sufficient. 
8.3
Statistical methods
The goal of this pilot application is to detect a signal of efficacy that would justify further investment. 
Treatment effects will be evaluated by conducting linear mixed models in SAS 9.4, with repeated 
measures nested within persons and with treatment (placebo vs. medication), ADHD symptoms, and 
ODD symptoms as covariates predicting whether  sleep onset latency (SOL) significantly decreases with 
treatment. We will also evaluate if improvements in SOL will be mediated through reductions in 
externalizing symptoms in the evening and examine for improvements in other sleep variables including 
WASO and frequency of nighttime awakenings.
9.0
Confidentiality, Privacy and Data Management 
See Research Data Plan Review Form for this entire section.
10.0 Data and Safety Monitoring Plan
Although the proposed study does not formally meet NIH requirements for the establishment of a Data Safety 
and Monitoring Board, a plan will be implemented. The principle investigator will oversee the daily safety of 
participants in the study. If a participating family has an urgent psychiatric concern (expressed suicidal ideation, 
serious aggression towards others), the principle investigator or the co-investigator (if the principle investigator 
is unavailable) can be paged 24 hours a day. The families will be provided with a 24-hour emergency contact 
number. If a serious adverse event occurs, one of the investigators will complete an Adverse Events Form and 
report the event to the IRB within 24 hours. They will gather information needed to investigate the event and 
review the adverse event report with the other investigative staff to determine subsequent action.
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10.1
Periodic evaluation of data
Participants will be evaluated by study physicians at first visit (baseline; 1 week), second visit (end of 
week 1), and third visit (endpoint; week 3).  Participants can be brought in for additional study visits as 
needed to assess tolerability or efficacy concerns.  Families will have ability to contact the principle 
investigator or co-principle investigator 24 hours a day.  Families will also be provided with a 24-hour 
emergency contact number.
10.2
Data that are reviewed
Data reviewed will include sleep onset latency, other sleep variables, side effects of study medication 
using the Pittsburgh Side Effect Rating Scale as well as spontaneous report, vital signs, concomitant 
medications, levels of ADHD /ODD symptoms and degree of parent rated irritability. 
10.3
Method of collection of safety information
Methods of collection of safety information include study visits (parent ratings, direct observation 
actigraphy) and direct feedback from children. 
10.4
Frequency of data collection
Safety data collection starts at the baseline visit (visit 2) . The same parameters will be collected at end 
of week 1 (visit 3) and final safety data collection also occurs at the end point visit (week 3). Families also 
have the ability to contact the principle investigator or co-principle investigator 24 hours a day for three 
weeks, resulting in the possibility of ad hoc data collection. Additional study visits can be scheduled as 
needed. 
10.5
Individuals reviewing the data
Study physicians and study investigators will be reviewing the data.  If a serious adverse event occurs, 
one of the investigators will complete an Adverse Events Form and report the event to the IRB within 24 
hours. They will gather information needed to investigate the event and review the adverse event 
report with the other investigative staff to determine subsequent action.
10.6
Frequency of review of cumulative data
All side effect data will be reviewed at the time of collection by MD study staff. 
10.7
Statistical tests
N/A Rates of side effects as captured on the PSERS within subjects between the medication and placebo 
will be analyzed by repeated measures ANOVA.
10.8
Suspension of research
Any participant experiencing a 50% worsening in sleep onset latency that cannot be corrected by 
lowering the prescribed dose will be discontinued from the study.  Further, study investigators will 
determine if a discontinuation from the study is appropriate due to any other adverse reaction to the 
Immediate Release Methylphenidate/Amphetamine.  While it is unlikely, as these participants will have 
had exposure to Methylphenidate treatment, the suspension of research may be required if severe 
adverse reactions including hypertension or other cardiac problems, other cardiovascular conditions, 
worsening behavioral problems including aggression and , psychotic symptoms, seizures, or acute visual 
disturbances. Participants may be withdrawn from the study at any point in time if safety concerns arise. 
, or safety concerns. 
11.0 Risks
1. Risk: The primary risk to participants includes any potential adverse reactions to the Immediate Release 
Methylphenidate (IR MPH) or Immediate Release Amphetamine (IR AMPH) treatment. The side effect 
profiles of IR MPH and IR AMPH are largely similar with the two medications primarily differing in their 
potency and duration (Pelham et al, 1999,  Greenhill et al, 2002). Common side effects include decreased 
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appetite and weight loss, irritability, sleep difficulties (however, it is theorized that many participants will 
experience decreased sleep latency secondary to better control of ADHD symptoms), increases in blood 
pressure and pulse, headaches, jitteriness, motor/verbal tics. Rare side effects include visual disturbances, 
serious cardiovascular problems, aggression, mania or psychotic symptoms, seizures, or visual disturbances. 
These rare side effects are generally confined to those with preexisting health problems in those realms (e.g. a 
personal history of structural heart defects, psychoses or mania). The risk of concerning side effects should be 
low as all participants will have had to be on a stable morning dose of a methylphenidate/amphetamine product 
for at least the past 30 days.  Hence, no participant will be newly treated with methylphenidate/amphetamine.  
Families will have 24 hour access to investigative staff should any adverse reactions occur, and medication status 
can be unblinded on an emergent basis if needed.   
2. Risk: Participants (children or family) may become distressed as a result of having to cease current 
Methylphenidate treatment for two days during the intake assessment process to determine study eligibility. 
Parents are allowed to pick what days this will be to minimize risk. Many parents routinely opt not to give 
medication on weekends and drug holidays are clinically prescribed to improve weight gain. Therefore, it is not 
uncommon for children to intermittently skip medication doses. There is no risk of withdrawal side effects with 
CNS Stimulants.
3. Risk: Participants (including child participant and families) may become distressed due to the increases in 
ADHD symptoms on placebo versus methylphenidate/amphetamine. All participants are randomized to receive 
treatment with placebo for 10 out of 21 of the study days. However, all will be continued on their morning dose 
of methylphenidate so there should be no difference in daytime symptom control. The increase in night time 
ADHD symptoms with placebo should be no different than pre study levels. 
4. Participants (children or family) maybe stressed due to time commitment and completing the necessary 
ratings and visits. We have selected relatively brief measurements to minimize this risk and participants can 
refuse to complete any measure they chose.
5. Risk: Primary caregivers may become distressed by the sensitive nature of some of the questions being asked. 
Most questions are similar to those encountered in routine clinical care for ADHD or sleep problems. They can 
refuse to answer any questions they are not comfortable with.
6. Risk: Loss of confidentiality.
12.0 Potential Benefits to Subjects and Others
12.1
Potential Benefits to Subjects
We anticipate a potential direct benefit to the parents and their child as a result of their participation in 
this research study.  Participants will receive an assessment by a mental health specialist that evaluates 
whether their child meets criteria for Attention Deficit Hyperactivity Disorder (ADHD) or one of its 
subtypes, as well as sleep disorder and/or other psychiatric conditions that commonly co-occur with 
these conditions (i.e.: depression, anxiety, oppositional defiance disorder, conduct disorder).  They will 
also be treated with Immediate Release Methylphenidate/Amphetamine (a FDA approved ADHD 
treatment) by clinicians who are experts in the management of ADHD, BIC and oppositional behaviors.  
All of these services will be provided free of cost.  Children can benefit from this study by displaying 
improvements in their sleep and behavior problems in the evening hours. Oppositional behaviors have 
been identified as a major cause of sleep problems in ADHD youth. The information gained from the 
study may also help parents, clinicians, and educators working with the children with sleep and 
behavioral problems to develop more effective intervention programs.  
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12.2
Potential Benefits to Others
Clinical science may gain further understanding in the alternate treatment methods of Behavioral 
Insomnia of Childhood in school-aged youth with ADHD.
13.0 Sharing Results with Subjects
Upon completion of the study, participants will be provided with their own treatment summary report, which 
includes the results of the initial diagnostic assessment, as well as specific feedback about the participant’s 
progress during the intervention. We will also share sleep logs and actigraphy data with the participants.
14.0 Subject Stipend (Compensation) and/or Travel Reimbursements
All services will be provided at no charge.  Parking is free at the HMC campus and the 22 Northeast Drive Clinic.  
Families will not be reimbursed for travel costs.  Families will receive a $50 gift card to a local store that offers 
child appropriate items (Walmart, Toys ‘r’ Us, Target), for completion of the endpoint measures.  The gift card 
being provided is to promote timely completion of assessment and to offset the cost of travel. The maximum 
compensation will be $50 per family.  Parents will only be compensated for completed assessment visits.
15.0 Economic Burden to Subjects
15.1
Costs 
Participating families will not be reimbursed for other expenses relating to the study such as 
transportation.  All treatment provided, study visits, telephone contacts, and physical and psychiatric 
evaluations will be provided free of charge.  Standard or emergency medical care provided outside of 
this study (taking the child to see their pediatrician) will not be covered or reimbursed for the 
participant or the participant’s parent(s)/guardian. For text reminders, regular text message rates and 
charges will apply as per the family’s mobile phone plan.  Families will not be reimbursed for any 
incurred costs related to the reminder text messages.
15.2
Compensation for research-related injury
It is the policy of the institution to provide neither financial compensation nor free medical treatment 
for research-related injury.  In the event of injury resulting from this research, medical treatment is 
available but will be provided at the usual charge.  Costs for the treatment of research-related injuries 
will be charged to participants or their insurance carriers.
16.0 Resources Available
16.1
Facilities and locations
Participants will be recruited from pediatric and psychiatry outpatient clinics within the Hershey medical 
Center. The Attention and Behavior Clinic (ADHD research site) is also housed at 22 NE Drive. 
Assessments will be completed  at 22 Northeast Drive, which has ample space for research.  Dr. Baweja, 
Dr. Waxmonsky, Dr. Waschbusch and Dr. Calhoun are on faculty at Penn State College of medicine in the 
Department of Psychiatry.
16.2
Feasibility of recruiting the required number of subjects
Over 3,000 children with Disruptive Behavioral Disorders are seen at Hershey Medical Center each year.  
Given the prevalence of Behavioral Insomnia of Childhood in such youth, recruiting a total of 38 
participants should not be problematic.
16.3
PI Time devoted to conducting the research
One calendar month
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16.4
Availability of medical or psychological resources
Treatment will be provided at the 22 Northeast Drive, Penn State Hershey Medical Group Psychiatry 
Clinic.  Parents interested in additional psychological or psychiatric services for their child(ren) may be 
directed to these additional services or can be directed to other providers in the area for their child’s 
mental health needs.  Any child that needs a more formal sleep assessment or other medical 
interventions for a sleep disorder will be referred to the HMC Pulmonary Sleep Center where Dr. 
Calhoun provides clinical services.
16.5
Process for informing Study Team
The study team can be updated during regularly scheduled meetings or any time through e-mail or 
phone.
17.0 Other Approvals
17.1
Other Approvals from External Entities
N/A
17.2
Internal PSU Committee Approvals
Check all that apply:
  Anatomic Pathology – Hershey only – Research involves the collection of tissues or use of pathologic 
specimens. Upload a copy of the Use of Human Tissue For Research Form on the “Supporting 
Documents” page in CATS IRB. This form is available on the IRB website at: 
http://www.pennstatehershey.org/web/irb/home/resources/forms
  Animal Care and Use – All campuses – Human research involves animals and humans or the use of 
human tissues in animals
  Biosafety – All campuses – Research involves biohazardous materials (human biological specimens 
in a PSU research lab, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA or 
gene therapy). 
  Conflict of Interest Review – All campuses – Research has one or more of study team members 
indicated as having a financial interest.
  Radiation Safety – Hershey only – Research involves research-related radiation procedures. All 
research involving radiation procedures (standard of care and/or research-related) must upload the 
Radiation Review Form on the “Supporting Documents” page in CATS IRB. This form is available on the 
IRB website at: http://www.pennstatehershey.org/web/irb/home/resources/forms
  IND/IDE Audit – All campuses – Research in which the PSU researcher holds the IND or IDE or 
intends to hold the IND or IDE.
  Scientific Review – Hershey only – All investigator-written research studies requiring review by the 
convened IRB must provide documentation of scientific review with the IRB submission. The scientific 
review requirement may be fulfilled by one of the following: (1) external peer-review process; (2) 
department/institute scientific review committee; or (3) scientific review by the Clinical Research Center 
Advisory committee.  NOTE: Review by the Penn State Hershey Cancer Institute Scientific Review 
Committee is required if the study involves cancer prevention studies or cancer patients, records and/or 
tissues. For more information about this requirement see the IRB website at: 
http://www.pennstatehershey.org/web/irb/home/resources/investigator 
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18.0 Multi-Site Research
N/A
19.0 Adverse Event Reporting
19.1
Adverse Event Definitions
19.2
Recording of Adverse Events
All adverse events (serious or non-serious) and abnormal test findings observed or reported to study 
team believed to be associated with the study drug(s) or device(s) will be followed until the event (or its 
sequelae) or the abnormal test finding resolves or stabilizes at a level acceptable to the investigator.
An abnormal test finding will be classified as an adverse event if one or more of the following criteria are 
met:
• The test finding is accompanied by clinical symptoms
• The test finding necessitates additional diagnostic evaluation(s) or medical/surgical intervention; 
including significant additional concomitant drug treatment or other therapy
NOTE: Simply repeating a test finding, in the absence of any of the other listed criteria, does not 
constitute an adverse event.
• The test finding leads to a change in study drug dosing or discontinuation of subject participation in 
the clinical research study
The test finding is considered an adverse event by the investigator.
Common side effects of IR MPH include appetite loss, headache, moodiness or irritability, problems 
falling asleep, feelings of nervousness, nausea, dizziness, stomachaches, skin rashes, drowsiness, motor 
movements (particularly of the mouth, jaw and tongue), and social withdrawal. Most side effects are 
mild and improve after says days on the medication, including problems falling asleep. The medication 
may also cause an increase in heart rate or blood pressure and can affect seizures in children with 
seizure disorders. Therefore, some children with heart problems or seizure disorder should not use this 
medication and will be determined as ineligible for the study.  A study physician will ask subjects if they 
have experienced any of these problems.  All subjects will have access to a 24/7 telephone number to 
report any of these symptoms or other adverse reactions as well.
 
19.3
Causality and Severity Assessments
The investigator will promptly review documented adverse events and abnormal test findings to 
determine 1) if the abnormal test finding should be classified as an adverse event; 2) if there is a 
reasonable possibility that the adverse event was caused by the study drug(s) or device(s); and 3) if the 
adverse event meets the criteria for a serious adverse event.
If the investigator’s final determination of causality is “unknown and of questionable relationship to the 
study drug(s) or device(s)”, the adverse event will be classified as associated with the use of the study 
drug(s) or device(s) for reporting purposes.  If the investigator’s final determination of causality is 
“unknown but not related to the study drug(s) or device(s)”, this determination and the rationale for the 
determination will be documented in the respective subject’s case history.
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19.4
Reporting of Adverse Reactions and Unanticipated Problems to the FDA  
All study drug will be used only for FDA approved purposes (to treat ADHD in children ages 6 to 12) 
without modification to its approved packaging. It will be administered in its unaltered commercially 
available form and dosed in accordance with the guidelines outlined in its respective FDA approved 
packaging. Therefore, according to FDA policy 21 CFR312.2b1, we do not believe that the study requires 
an IND.  An RQA consult also determined that an IND was not necessary.
19.4.1 Written IND/IDE Safety Reports
N/A
19.4.2 Telephoned IND Safety Reports – Fatal or Life-threatening Suspected Adverse Reactions
N/A
19.5
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) 
experienced by a subject or other individual, which in the opinion of the investigator is determined to be 
(1) unexpected; and (2) probably related to the research procedures. Harms (adverse events) will be 
submitted to the IRB in accordance with the IRB policies and procedures.
19.6
Unblinding Procedures
If the need arises, research staff will contact the research pharmacy to identify the medication that was 
given on a specific date. Research staff will be able to access the list outside of pharmacy hours if 
emergently needed.
19.7
Stopping Rules
N/A
20.0 Study Monitoring, Auditing and Inspecting
20.1
Study Monitoring Plan
20.1.1 Quality Assurance and Quality Control
N/A
20.1.2 Safety Monitoring
N/A
21.0 Future Undetermined Research: Data and Specimen Banking
N/A
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