Sleep Management And Recovery After Traumatic Brain Injury in Kids (SMARTKids): Evidence for Targeting Sleep to Improve Outcomes
Phase: PHASE2
Conditions: Traumatic Brain Injury, Critical Illness, Sleep
Sponsor: Oregon Health and Science University

 
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Study Protocol 
 
 
1. Protocol Title 
Sleep Management And Recovery after Trauma in Kids (SMART-Kids): Melatonin Pilot Trial 
NCT04932096 
IND reference number 157247 
 
PI: Cydni N. Williams, MD, MCR 
                     707 SW Gaines St, CDRC-P 
 
       Oregon Health & Science University 
 
       Department of Pediatrics, Division of Pediatric Critical Care 
                     Portland, OR 97239 
                     (503) 494-5522 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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2. Objectives 
This is a randomized controlled phase II intervention trial evaluating early melatonin and a sleep 
educational intervention versus placebo following pediatric traumatic brain injury (TBI). No 
changes to typical TBI care will be made. This single center trial will focus on feasibility and 
acceptability outcomes of a real world pragmatic sleep intervention frequently utilized in the 
outpatient setting among pediatric TBI patients when employed earlier in the recovery process 
during hospitalization. We will also obtain data on effectiveness to reduce sleep disturbances at 
30-day outcomes assessment to help inform a larger trial that would be powered to evaluate 
effectiveness among a heterogeneous population.   
 
3. Background 
Sleep wake disturbances (SWD) affect over 50% of the 50,000 children surviving critical care 
hospitalization for traumatic brain injury (TBI) each year in the United States.[1-5] SWD are known to 
significantly impair quality of life and persist for years after TBI of all severities and in children of all 
ages.[6-13] SWD place these children at risk for long-term adverse health outcomes as recognized in 
Healthy People 2020.[14-16] However, interventions for SWD after pediatric TBI are poorly studied and 
clinicians are left with little evidence base to guide care for this debilitating morbidity after TBI.[17-19] 
Despite known benefits of healthy sleep on brain development and healing,[20-25] it remains unknown 
how SWD impact recovery in other physical, cognitive, and psychosocial outcomes after pediatric TBI, 
especially among children hospitalized with complicated mild, moderate, and severe injuries. Our 
research shows 52% of these TBI patients have SWD and 84% with SWD have phenotypes consistent 
with insomnia and circadian disturbance, though multiple SWD phenotypes often coexist.[5] SWD may 
be particularly important in recovery of executive functions after TBI that are linked to poor academic 
and functional outcomes.[11, 26-29] Therefore, we will conduct a pilot randomized controlled trial of an 
early sleep management intervention (melatonin and a sleep education handout) to determine 
acceptability and feasibility of an intervention directly applicable to the pediatric TBI population. We will 
also explore clinical effectiveness outcomes of this real-world intervention to provide preliminary data 
for a larger trial with the long-term goal of improving quality of life and multimodal outcomes through 
sleep interventions. 
 
Early sleep intervention may be particularly important for children suffering TBI as sleep 
promotes neuronal healing and reduces inflammation that could maximize functional 
recovery.[30-35] However, two recent systematic reviews show no studies evaluating 
interventions to improve sleep after TBI hospitalization in children.[17, 36] Melatonin and 
behavioral/educational interventions are safe, first line therapies for multiple SWD phenotypes 
in pediatric primary care and sleep clinics.[37-46] In our multidisciplinary Pediatric Critical Care 
and Neurotrauma Recovery Program at OHSU, standard clinical care for SWD after TBI in the 
outpatient setting includes melatonin and sleep educational interventions used together as first 
line treatments for difficulty initiating and maintaining sleep starting at the first outpatient visit 
typically 4-6 weeks after hospital discharge (see uploaded example of actual clinical 
recommendations in supporting documents). Our research shows children with TBI have high 
rates of difficulty with onset and maintenance of sleep.[5] Our recently accepted publication 
showed that SWD occurred in 2/3 of pediatric TBI patients and were associated with 
significantly worse objective and subjective measures of cognitive function 1-3months after 
pediatric TBI hospitalization; interestingly in this cohort of 131 children, 12% of patients had 
already started melatonin after hospital discharge prior to the appointment without a clinical 
prescription, and we prescribed melatonin together with sleep education targeting behavioral 
modifications to address sleep newly in 43% at the clinical visit.[47] This is also in line with 
research showing up to 1 in 17 school aged children from the general population have used 
melatonin more than once a week within the last 6months.[48] Both melatonin and educational 

 
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sleep  interventions targeting improvements in sleep hygiene, which are most often used in 
combination to provide the greatest benefit, are shown to improve SWD in multiple other 
pediatric populations, including improvements in sleep latency, efficiency, and duration directly 
applicable to our TBI cohort.[37, 38, 40, 42, 44, 46, 49-54] In most instances, melatonin is 
utilized in the 1-2 hours before bedtime for soporific effects in pediatric patients in conjunction 
with education about the importance of a good sleep routine, environmental changes to 
promote sleep, and recommendations for behavioral modifications to promote sleep.[51, 55] 
Melatonin levels and circadian rhythms are known to be altered in hospitalized patients and TBI 
patients, and could contribute to ongoing circadian disturbance, which may be another way 
melatonin could be helpful.[56-61] Additionally, melatonin has analgesic, anti-oxidant, anti-
inflammatory, and anti-apoptotic effects relevant to TBI outcomes.[33, 34, 36, 44, 62-69] 
Inflammation in particular is chronic after TBI, is linked to SWD including insomnia, and targeting 
inflammation may improve SWD.[31, 34, 70-73] A randomized trial in 33 adults with TBI and 
SWD approximately 46 months after injury showed melatonin improved subjective sleep quality, 
fatigue, and sleep efficiency on actigraphy compared to placebo.[74] A retrospective study of 
adolescent concussion showed 67% reported improved sleep subjectively with melatonin 
prescribed in clinic.[75] A recent randomized controlled trial in outpatient pediatric concussion 
in children aged 8-18years found no evidence of improvement in overall post-concussive 
symptoms, but did improve sleep efficiency on actigraphy, and there were no serious adverse 
events.[76, 77] Improved sleep latency and duration with melatonin after non-traumatic 
pediatric acquired brain injuries are also reported.[44, 46, 78] A recent randomized trial of 
pediatric cancer survivors, including those with brain tumors, showed 3mg of melatonin 
improved aspects of sleep and cognition, and also noted that the addition of interventions 
targeting behavioral changes based in cognitive behavioral therapy for insomnia (CBT-I) could 
have improved gains further based on results in prior trials.[79] 
A 2022 systematic review that included analyses of recent randomized controlled trials in 
pediatric neurodevelopment populations reported no adverse events with short term <3month 
use and few mild side effects even with prolonged usage in pediatric patients.[80] While some 
healthy children may respond to behavioral interventions targeting sleep hygiene alone, those 
with neurodevelopmental and neurologic diagnoses are more likely to need additional 
interventions, with melatonin combination being the first line treatment to address sleep 
latency and maintenance.[42, 52, 54, 81] It should be noted that TBI patients have high rates of 
baseline neurodevelopmental disorders, which also increases the risk for post-traumatic SWD 
after hospital discharge.[47, 82] A recent literature review and expert consensus panel 
convened in 2019 additionally endorsed the safety of melatonin and recommended use in 
conjunction with educational and behavioral interventions (sleep hygiene, routines, family 
education, etc) in children; this review specifically highlighted the safety of melatonin in short 
and long-term use in pediatric patients and the fact that melatonin is used in conjunction with 
sleep education targeting improved sleep hygiene.[83] A recent study also showed a >200% 
increase in the use of melatonin among hospitalized children of all diagnoses in a large tertiary 
academic children’s hospitals between 2016 and 2020, showing the increasingly ubiquitous use 
of melatonin in pediatrics; most of the doses were scheduled nightly during hospitalization, 
were used in ICU and non-ICU areas, ages ranged from 2months of age to >18years of age, doses 
ranged from <1mg to 30mg depending on age and indication targeted.[84] A dose finding trial in 
pediatric oncology showed melatonin was well tolerated at doses up to 0.3mg/kg (max 
20mg).[85] Melatonin and sleep educational interventions are most often used in conjunction, 
though the combination has not been studied for SWD in hospitalized pediatric TBI populations. 
These interventions are promising given safety and pleiotropic effects with respect to sleep 
onset, maintenance, and anti-inflammatory properties, as well as potential for easy 
dissemination and implementation, directly applicable to the pediatric TBI population. This 

 
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study will primarily evaluate feasibility and acceptability of a real-world sleep intervention 
frequently employed in the pediatric TBI population within the outpatient setting. We will also 
explore whether earlier inpatient employment of standard SWD interventions (melatonin and 
sleep education) commonly administered in the outpatient setting can provide benefit when 
employed earlier in the disease course as an adjuvant to clinical TBI care. 
4. Study Design 
This is a pilot randomized controlled phase II intervention trial evaluating early melatonin and sleep 
education via handouts versus placebo following pediatric traumatic brain injury (TBI) in two parallel 
study arms. This single center trial will focus on feasibility and acceptability outcomes, but will also 
obtain data on clinical effectiveness to reduce sleep wake disturbances at 30-day outcomes assessment. 
Sleep disturbances (with questionnaires and actigraphy data from Fitbits), feasibility (with clinical data 
collection, participant survey), and acceptability (survey, medical chart review) outcomes will be 
collected. 
 
The intervention of this study uses a dietary supplement (melatonin) and an educational intervention 
administered via handouts. This study is not designed to evaluate melatonin’s therapeutic efficacy or 
potential to diagnose, cure, mitigate, or otherwise treat a specific medical disorder, only to evaluate 
potential benefits to the bodily function of sleep when used with sleep education.  The combined 
intervention of melatonin and sleep education was designed to mirror real world clinical care employed 
in this population within the outpatient setting in order to be generalizable to a heterogeneous 
population that is representative of the pediatric TBI population; therefore, our trial is designed to be 
pragmatic and will be exploring effectiveness outcomes for SWD relevant to this population, rather than 
efficacy of any one part of the intervention. A primary focus will be feasibility and acceptability 
(including intervention usage) to inform a larger longitudinal trial that would be needed to account for 
unavoidable population heterogeneity in clinical characteristics and adherence to intervention 
recommendations within the clinical setting. 
 
5. Study Population 
 
a. Number of Subjects 
We expect to enroll between 30-50 patients based on eligibility over 2.5 years of recruitment. This 
estimate is based on the most recent hospital admissions data since the start of the COVID-19 pandemic 
estimating approximately 100 patients will qualify for the study over 2.5 years. Participants will be 
randomized 1:1 to receive the intervention. Recruitment and retention will be assessed during the trial 
as outcomes.  
 
b. Inclusion and Exclusion Criteria 
Children ≥6 years and <19 years of age admitted with TBI (defined as injury to the head from 
external forces with severity mild, moderate, or severe classified by Glasgow Coma Scale) will be 
included.  
 
Children under the age of 6 years will be excluded due to increased variability in baseline sleep 
patterns, daytime napping, and lack of standardized tools identifying sleep outcomes between 
children younger and older than 6 years.  Patients over age 18 years will be excluded as they are 
primarily treated in adult care units and the study focus is pediatric. Patients unable to tolerate 
enteral medications within 72 hours of hospital admission, as defined by the clinical care 
Attending Physician, will be excluded from the study. Patients undergoing dialysis, requiring 
extracorporeal life support, or with significant liver dysfunction (defined as aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) more than 2 times the upper limit of 
normal for age) will be excluded. Patients about whom the Attending Physician has any safety 

 
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concerns regarding use of melatonin as per clinical judgement will be excluded from the study. 
Patients with abusive trauma will be excluded.  Suspected or known prisoners are excluded. 
Pregnant patients are excluded. There will be no requirement for contraception during the trial 
in female patients of child-bearing age. Patients must have a parent or guardian with whom they 
reside in order to participate in the study given the parent-reported measures used for 
outcomes.  
 
There is inherent heterogeneity in the pediatric TBI population, and this study is designed to be 
inclusive of the representative clinical population, including those with pre-existing conditions. 
Given the ubiquitous use of melatonin in pediatric clinical care and research studies in a variety 
of pediatric populations with medical, developmental, and psychiatric disorders, no patients will 
be excluded for underlying medical conditions or concomitant medication use outside of the 
above exclusion criteria unless clinical judgement by the Attending Physician on the clinical care 
team would preclude use of melatonin for safety concerns. 
 
Potential participants will be screened on arrival through the OHSU Emergency Department (all 
traumas, suspected traumas, and trauma referrals from other institutions are evaluated by the 
Trauma Surgery team in the Emergency Department per OHSU policy prior to admission). 
Medical records will be reviewed by the study team to determine eligibility; a waiver of consent 
under “Activities Preparatory to Research” for participant eligibility determination by research 
coordinators will be obtained. Research coordinators with the Trauma Research Group are 
present in the Emergency Department and are available to screen all TBI admissions for 
inclusion into active research studies 24hours/day. Screening information regarding 
inclusion/exclusion criteria will be retained for further analysis of recruitment outcomes. 
  
c. Vulnerable Populations 
The aims of this study are entirely focused on children ≥6 years to <19 years old.  Inclusion of children is 
appropriate given the proposal focus on sleep outcomes in pediatric traumatic brain injury.  Traumatic 
brain injury is a significant problem for children, including the leading cause of death and disability over 
1 year of age. Dr. Williams is a Pediatric Critical Care physician with significant expertise in caring for 
children of all ages with critical illnesses, including traumatic brain injury, during the acute 
hospitalization.  Dr. Williams also has unique expertise in the longitudinal care of these children after 
discharge, directing the Pediatric Critical Care and Neurotrauma Recovery Program. Age will be 
evaluated as a covariate in the analysis of both aims. Pregnant patients and prisoners are excluded. 
 
d. Setting 
Patients will be recruited from OHSU and Doernbecher Children’s Hospital 
 
e. Recruitment Methods 
Screening: Children with traumatic brain injury (TBI) will be screened for inclusion in the study 
by the Trauma Research Group (TRG) on admission to Oregon Health and Science University or 
Doernbecher Children’s Hospital. Research coordinators with the TRG are available to screen all 
TBI admissions for inclusion into active research studies 24 hours per day. Screening activities 
will take place under a HIPAA waiver per the “Activities Preparatory to Research” policy at 
OHSU. Given the extensive experience and training of the TRG, we expect very few if any screen 
failures of TBI admissions, and this will be actively monitored throughout the study period.  
Recruitment Procedures: Recruitment will be maximized by using consistent trained staff within 
the TRG that have extensive experience consenting subjects and surrogates for research, 
including critically injured children. The recruitment process will be overseen by Dr. Williams, a 
Pediatric Critical Care physician, with expertise in caring for critically injured children. TRG staff 

 
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are trained and mindful of the critical nature of traumatic brain injury and will ensure the 
appropriate time and conditions for obtaining informed consent. Individual staff are monitored 
to ensure adherence to TRG standard operating procedures and study protocols.  
The appropriate time to approach patients will be determined by study staff and clinical care 
staff, and consent will be obtained within 72 hours of Pediatric Intensive Care Unit admission to 
ensure starting the intervention as early as possible. Delaying consent for critically ill patients 
will not adversely affect the study outcomes, but will allow for acute stabilization of patients 
prior to consideration of study inclusion, ensure ability to administer enteral medications, and to 
allow for determination by the primary clinical care team of a patient’s likelihood of survival. 
Consent procedures will be reviewed at least quarterly during TRG coordinator meetings to 
ensure ongoing consistency. The minimum goal set for recruitment is 50% of eligible patients.  
Retention: All patients consenting for inclusion will have phone, address, email contact 
information collected at time of consent.  Outcomes will be obtained at 1-month follow-up as 
described.  
Participants will be compensated $25 for time related to completion of study procedures at 
baseline and $50 for time to complete study procedures at 30-days (total $75 per participant). 
The FitBit account will be transferred to their participant preferred email account at study 
completion (cutting off research team access automatically) and can keep the FitBit device. 
f. Consent Process 
This intervention study is considered more than minimal risk, but with potential to directly benefit the 
participant and uses a low-risk intervention frequently employed in the care of pediatric TBI patients in 
the outpatient setting. Therefore, written informed consent for study inclusion will be obtained from 
one parent or legal guardian able to provide consent for minors, and those <18 years meeting criteria 
under Oregon law to be considered adults and unable to provide consent themselves. As above, 
participants must have a parent or legal guardian with whom they reside in order to participate. 
Additionally, acute TBI is likely to affect participants’ ability to provide informed consent. Therefore, 
minors will not be allowed to consent for themselves during this study, though we will require assent for 
those able to provide. Children who come of age or meet criteria under Oregon law to be considered 
adults during the study period will be re-consented for study inclusion.  The logistics will be determined 
according to the convenience of the families considering enrollment. Every effort will be made to ensure 
that the consent discussion occurs in a private environment, when the subject/parent/guardian duress is 
minimized to the extent possible. Participants will be approached for the study within 72 hours of 
admission, after acute stabilization from the critical illness (defined by clinical care Attending Physicians 
assessment as likely to survive to hospital discharge and able to tolerate enteral medications), either 
while in the PICU or on the acute care ward prior to discharge. All consent forms, documentation, and 
discussion will be conducted in the parents’ native language. We are aware that, under the 
circumstances, the study often needs extra-careful and repeated explanation. We routinely follow our 
explanation of the study protocol by a period for parents to ask questions, but in addition we also ask 
the parents questions to gauge their level of understanding. If it is our impression that parents remain 
unclear about aspects of the study, we spend extra time clarifying these specific issues. In this manner, 
all elements of the informed consent process will be discussed until the investigator is assured of the 
subject’s or parent’s (and, when appropriate the child’s) full understanding. 
 
Assent from children ≥7years of age for study inclusion will be obtained when possible:  
• 
Children younger than 7 years: Assent is not required because the subjects are so young 
they cannot reasonably be consulted. However, a simple verbal explanation of the study 
procedures should be given if appropriate.  

 
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• 
Children ages 7 – 14 years: Researchers may obtain assent verbally and document this 
on the consent form or elsewhere in the research record, or researchers may ask the 
subject to sign an assent form after discussing the study with the subject at a level 
appropriate to the subject’s understanding. Researchers will use the OHSU assent 
template.  
• 
Children ages 15 – 17 years: The subject may sign the consent form along with his or her 
parent(s) or guardian as documentation of assent. A separate assent form is not needed. 
 
For non-English speaking participants, we have 24/7 available translators over the phone that will assist 
with the consent process. We will submit short consent form(s) for IRB review and approval as 
appropriate. An interpreter will assist with the initial consent process and subsequent study visits for all 
non-English speaking subjects. 
 
Other than screening procedures described above, no modifications to the written consent process will 
be used.  
 
6. Procedures Involved 
Data Collection: Patients meeting inclusion criteria (see Eligibility Criteria) will be approached within 
72hours of hospital admission to provide written consent and assent where appropriate. Parents will be 
asked to complete “baseline” assessments retrospectively to reflect the patient’s pre-injury status at the 
time of consent. Additional information will be collected by the study team from parents via survey and 
medical record review for demographic and clinical variables. Our goal recruitment and completion is for 
30-50 patients.  
Randomization: Patients will be randomized 1:1 to intervention and control arms using a covariate 
adaptive design through the randomize.net website. Given heterogeneity in age and TBI severity, we 
aim to balance these patient characteristics across the arms with a relatively small sample size. A 
covariate-adaptive design will achieve better balance than one based on block stratification, as such a 
scheme will increase a subject’s probability of being assigned to the arm that improves overall balance 
in age and TBI severity (Glasgow Coma Scale Score groups: mild 13-15, moderate 9-12, severe ≤8). 
Initially, we will assign patients 1:1 to each arm by simple randomization, until six patients have been 
enrolled in each arm; this will allow us to collect sufficient information on covariates and determine the 
distribution of age and TBI severity in each arm. Once this criterion has been met, the Pocock-Simon 
minimization algorithm will be implemented and subsequent patients will be randomized with a 
probability of 0.85 to the arm that lowers overall imbalance in age and TBI severity. All patients will be 
randomized within 72 hours of hospital admission. 
Intervention: All patients will receive standard clinical care for TBI regardless of study arm. Patients 
randomized to the intervention will receive a bundled sleep intervention consisting of melatonin and 
sleep education via a handout provided in discharge paperwork. Melatonin doses of 3mg and 5mg will 
be administered as part of the intervention arm in standard doses based on patient weight to target 
approximately 0.1mg/kg and not to exceed 0.2mg/kg. Melatonin will be administered on the first night 
following consent, 1 hour prior to habitual bedtime, and continued nightly for 30-days. Each participant 
will start the melatonin or placebo intervention within 96 hours of hospital admission, varying with time 
of admission and consent. Patients randomized to receive the intervention will be given a written sleep 
education handout developed with age-based recommendations from the American Academy of Sleep 
Medicine and access to web-based sleep educational resources developed from similar materials used in 
the care of pediatric brain injury patients within the outpatient setting.  
The handouts delivered with discharge paperwork will be incorporated into the discharge instructions 
section within the electronic medical record by a research assistant. Handouts contain resources 
outlined below educating patients and families on the importance of sleep, sleep hygiene, sleep 

 
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routines, environmental changes to facilitate sleep, and relaxation techniques; the handouts were 
adapted from standard care provided in our outpatient program for TBI management (see details 
below). Further, a study in a pediatric ICU cohort designed to directly compare modes of educational 
intervention delivery, and included parents of pediatric TBI patients, recently showed an educational 
handout was just as effective as a scripted conversation or a short video when attempting to educate 
families about morbidities after hospital discharge, but the handout was the most sustainable and 
supported by hospital staff.[86] 
Participants randomized to the control arm will receive placebo (microcrystalline cellulose) and the 
sleep education handout delivered with discharge paperwork as above. All patients will receive clinical 
care as usual for management of TBI. All traumatic brain injury patients at OHSU receive referrals for 
clinical follow up with the Pediatric Critical Care and Neurotrauma Recovery Program (PCCNRP); other 
referrals made to outpatient programs are made on an as needed basis depending on type of TBI and 
other concurrent injuries or morbidities identified during hospitalization. While in the hospital, current 
standard of care treats morbidities after TBI as needed and varies by clinical provider; there is no 
standard for treating sleep problems in the hospital. As outpatients, all hospitalized pediatric trauma 
patients at OHSU are referred to the PCCNRP clinic 4-6weeks after discharge. At this outpatient visit, a 
comprehensive assessment in physical function and morbidity is made by Dr. Cydni Williams (Pediatric 
Intensivist), which includes assessment of sleep; a brief neuropsychological assessment of cognitive 
function and a comprehensive psychological assessment are made by Dr. Trevor Hall (Pediatric 
Neuropsychologist). Given this study’s intervention is designed for 30days and we plan to make no 
changes to clinical care, all patients in the trial will still have access to these evaluations at clinic 
appointments 4-6weeks after discharge.  
As noted above, we see high rates of SWD with regard to initiation and maintenance of sleep and our 
first line recommendations at these outpatient appointments for pediatric TBI patients are a 
combination of melatonin supplementation (at doses of 1mg to 10mg targeting soporific effects 
depending on child age and size) and sleep education targeting improvements in sleep hygiene, 
routines, relaxation, and environment to facilitate sleep delivered in conjunction with each other. The 
sleep education recommendations are included in a paper report of the entire visit that includes 
education about the importance of sleep, sleep hygiene, environmental changes to promote sleep, and 
relaxation techniques. This report also includes links to videos developed by Dr. Cydni Williams, Dr. 
Trevor Hall, and Dr. Andrew Riley utilizing the CBT-I principles (links to videos found in supplemental 
documents). Both the written information and video links provided in clinic were used to develop the 
proposed sleep education handout portion of this study’s intervention delivered at hospital discharge in 
this trial; the videos for the study were placed in Qualtrics to aid in tracking usage for the study and 
generating links and QR codes for easy access, and the written information was formatted for the study 
to provide concise information across a broad population and visual appeal for children or teens. 
Participants and study staff assessing outcomes will be blinded to intervention status. Research 
assistants on the study staff will add the sleep education handouts with video links to discharge 
instructions to be delivered by the bedside nurse in concurrence with clinical care. The intervention was 
designed this way to increase feasibility and generalizability for the future by providing a means of 
information dissemination that could be easily and widely adopted if effective within different health 
systems in conjunction with clinical care. This research assistant will be notified by REDCap when a 
participant is enrolled, and will place instructions in the discharge section of the electronic health record 
that is automatically printed at discharge, without interaction with other study team members or 
families. Additionally, this portion of the intervention will be delivered at hospital discharge concurrent 
with clinical care to improve generalizability in future work by limiting change to institutional care 
practices. The sleep handout will be delivered in conjunction with standard discharge instructions 
provided to all TBI patients and other care will remain per our institutional TBI standards directed by the 

 
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patient’s care team (an example of these standard TBI discharge instructions are uploaded in supporting 
documentation). 
Outcomes: We will include measures of feasibility, acceptability, and effectiveness. See Table 1 for 
summary of outcomes and schedule of collection. Outcomes will be assessed at hospital discharge, and 
a study visit at 30 days ±17 days. 30-day outcomes assessments will be defined from the time of study 
intervention initiation. The primary outcomes will be measures of feasibility and acceptability, with 
exploration of effectiveness in this pilot trial. Quantitative measures of recruitment and retention 
(feasibility), adverse events and utilization (acceptability), and total score of the Sleep Disturbances 
Scale for Children (SDSC) at 30-days (clinical effectiveness) will be used. Outcomes will be collected by 
the study team over the phone, via chart review, or via electronic survey administered through REDCap. 
Secondary and other outcome measures will be collected by activity monitor, chart review, survey, sleep 
questionnaire, and actigraphy devices. Fitbits will be worn continuously during the 30 day study period 
except when removed for charging the device.  
Text messaging will be used for system generated reminder prompts such as “Please sync your device"; 
or if battery is low, "Please charge your battery” during the 1-month study period while participants 
wear the Fitbit. Text messaging functions require sharing of participant phone numbers with the 
Fitabase platform and Twilio, Inc. 
Feasibility benchmarks will be assessed every 6 months during the trial. If feasibility benchmarks are not 
met, study procedures and the protocol will be reviewed using input from stakeholders and preliminary 
data to determine if changes are warranted.  
Table 1. Outcomes Evaluation and Analysis for Melatonin Trial 
 
Outcome (time 
collected) 
Measurement or Assessment Tool 
Analysis  
Feasibility Outcomes 
 
*Recruitment (6-
monthly feasibility 
reviews) 
Number subjects consented/approached; goal >50% 
Descriptive percent 
*Retention (6-monthly 
feasibility reviews) 
Quantitative Number completed/consented; Goal 
>90% 
Descriptive percent 
Screen failure (6-
monthly feasibility 
reviews) 
Number approached/eligible patients; expect <<5%; 
eligible patients will be derived from the OHSU 
Trauma Registry and compared to study logs 
Descriptive percent 
Reasons for 
Participation/ Non-
participation (time of 
approach/consent) 
Qualitative response to survey: “Please describe 
reasons you chose [not to or to] participate in this 
research study”; “Could the study team do 
something different in the future to increase 
chances you would participate in future studies?” 
Thematic analysis 
Reasons for drop-out 
(30-day) 
Qualitative response to survey: “We would like to 
know how we can improve our study in the 
future. Please tell us your reasons for leaving the 
trial”; “How could the study team have assisted 
you better in completing the trial?” 
Thematic analysis 
Adherence (30-day) 
Pill counts: adherent if ≥75% prescribed pills are 
taken at the follow-up study visit; will be counted 
as unknown if pill count not available 
Sleep  tracking usage: actigraphy data and sleep 
diaries will be compared to age based 
recommendations; actigraphy counted as 
Descriptive percent; Chi-
square to compare 
intervention arms 
Descriptive percent; Chi-
square to compare 
intervention arms 

 
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adherent if device worn for ≥5 nights 
consecutively; we will assess sleep routines 
through actigraphy; will be counted as unknown if 
did not participate in the actigraphy portion 
Quantitative survey: “How many nights each week did 
you take the study medication since discharge?” 
None, 1-3, 3-4, 5-7, All  
Quantitative survey response: “Did you receive sleep 
education with your hospital discharge 
paperwork?”; choices of a) did not receive 
discharge paperwork; b) I did not receive any 
sleep education at discharge; c) I received it, but 
did not use it; d) I received it, but did not find it 
helpful; e) I received it, and found it helpful; 
responses to this question will also be compared 
with the discharge instructions within the 
electronic health record to determine if the 
resource was provided as intended. 
 
 
 
 
 
 
Descriptive percent; Chi-
square to compare 
intervention arms 
Acceptability Outcomes 
 
*Adverse Events 
(discharge,  30-day) 
Qualitative response to survey: “Did you have any 
new medical problems since the last study visit?” 
Quantitative yes/no response: “Did you have any of 
the following symptoms since the last visit” 
a. Nausea 
b. Vomiting 
c. Diarrhea 
d. Drowsiness 
e. Fatigue 
f. Headache 
g. Behavioral changes 
h. Vivid dreams 
i. 
Nightmares 
j. 
Waking up at night 
k. Itchy skin 
l. 
Rash 
m. Appetite changes  
n. Bodily pain or aches 
o. Chest pain 
p. Enuresis or bedwetting 
q. Dizziness 
r. Tinnitus or ringing in the ears 
s. Feeling cold 
Evaluation of medical record, patient assessments to 
quantify adverse events and unexpected 
problems collected as a dichotomized yes/no and 
number of events 
Thematic analysis 
 
 
Descriptive percent and 
mean with standard 
deviation; Chi-square 
(yes/no) and Mann-
Whitney U test 
(continuous) to 
compare intervention 
arms 
Satisfaction (30-day) 
Quantitative rankings on a likert scale survey: 
experiences with the study overall, consent 
process, study team, study intervention, 
questionnaires, Actigraphy devices, care received 
Descriptive median and 
interquartile range; 
Mann-Whitney U tests 

 
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clinically in the hospital, care received clinically 
after hospital discharge 
Qualitative response to survey: “If you were provided 
sleep education, and did not use it or find it 
helpful, please describe reasons:"; “If you were 
provided sleep education, and found it helpful, 
please describe how you utilized the resources”; 
“How can the study team improve the experience 
of participants in future studies” 
to compare 
intervention arms 
 
Thematic analysis 
Reasons for Non-
adherence (30-day) 
Qualitative responses to survey: “Please describe 
reasons for not taking the study medication”; 
“Please describe reasons for not using the sleep 
educational resources provided at hospital 
discharge”; “How could the study team improve 
the design of the study in the future”; “How could 
the study be improved in the future” 
Thematic analysis 
Exploratory Clinical Effectiveness Outcomes 
 
*Sleep wake 
disturbance (Baseline, 
30-day) 
Sleep Disturbances Scale for Children (SDSC) total 
score 
Descriptive mean and 
standard deviation; 
linear regression to 
compare intervention 
arms 
Sleep wake disturbance 
phenotypes (Baseline, 
30-day) 
SDSC subscale scores, Children’s Chronotype 
Questionnaire, actigraphy measures (total sleep 
time, sleep onset latency, wake after sleep onset, 
sleep efficiency, night sleep:total sleep time, sleep 
onset, sleep offset, daytime sleep episodes, 
duration of daytime sleep) 
Descriptive mean and 
standard deviation; 
linear regression to 
compare intervention 
arms 
Global health (Baseline, 
30-day) 
Pediatric Quality of Life Inventory (PedsQL) scales for 
core, fatigue 
Descriptive mean and 
standard deviation; 
linear regression to 
compare intervention 
arms 
Emotional health 
(Baseline, 30-day) 
PROMIS measures for anxiety and depression 
Descriptive mean and 
standard deviation; 
linear regression to 
compare intervention 
arms 
Physical function 
(Baseline, 30-day) 
PROMIS measures for pain; Functional Status Scale 
Descriptive mean and 
standard deviation; 
linear regression to 
compare intervention 
arms 
Cognitive function 
(Baseline, 30-day) 
Behavior Rating Inventory of Executive Function, 
Second Edition 
Descriptive mean and 
standard deviation; 
linear regression to 
compare intervention 
arms 
*Primary outcomes 
 

 
Page 12 of 20 
 
Subjects can withdraw from the study at any time, including discontinuation of the intervention. 
Subjects can choose to withdraw consent for use of their data during the study, and they will be fully 
removed. Subjects can also choose to withdraw from the intervention, but continue in the study where 
their data will be collected and analyzed. 
 
7. Data and Specimens 
Data and protected health information will be safeguarded in multiple ways. First, all study forms 
will include only a study ID number.  Actigraphy devices will be configured with only an ID number 
and will not store any identifiers. The key to study ID and patient identifiers will be maintained by 
the PI in a secure REDCap database that is password protected and hosted on the OHSU secure 
server.  All study data will be inputted into REDCap by members of the study team.  The PI will 
maintain the REDCap database and provide access only to study team members.  All exports of data 
from REDCap will be coded.  
All potential physical discomforts related to actigraphy devices will be minimized by allowing 
participants to remove the device if discomfort occurs and to withdraw from this portion of the 
study if desired. The actigraphy data will be collected using Fitbit devices. 
The Fitbit mobile app and device require the creation of individual accounts with Fitbit for all study 
participants within the Fitbit app on a smart phone or tablet. Participants will be asked to use an 
email address of their choosing and accept Terms and Conditions for use of the Fitbit app.  The data 
collected from the Fitbit devices will NOT be integrated with the medical record of the patient or 
used for clinical decision making.  FitBit data will be collected through syncing with the FitBit app on 
a smart phone or tablet at least weekly by the participant. The Fitabase platform will be used to 
remotely collect real-time physical activity and sleep data from study participants’ Fitbit accounts, 
and also to send personalized text messages to participants’ cell phones. Participants will be asked 
to accept the Fitabase Terms and Conditions for linking with the Fitbit App. Fitabase is a secure 
password-protected web-based platform hosted in a HIPAA-compliant server. Fitabase comprises 
user-friendly visualization and data exportation tools that allow key research personnel to view 
participants’ Fitbit data in the form of graphs every time participants sync their wearable tracker 
with the Fitbit mobile app. Study participants will not have access to Fitabase; they will only interact 
with the Fitbit mobile app and activity tracker. The text messaging feature is integrated with 
Fitabase and utilizes Twilio’s application programming interface to send messages via the SMS 
protocol. Participants will be consented to utilize their smart phone devices for syncing with the 
Fitbit app and to receive text messages from the platform to serve as reminders to sync devices and 
to utilize the online resources for those in the intervention phase. The only identifier shared with 
the Fitabase platform and Twilio, Inc. is the telephone number for the smart phone device the 
participant consents to utilize. Participants will be asked to use and email address of their choosing 
to create an account within the Fitbit App.  
All risks associated with the intervention will be minimized by allowing participants to discontinue 
the intervention at their discretion and the study team will regularly assess adverse effects of the 
intervention.  
If participants suffer any unforeseen harms including psychological, emotional, physical, they will be 
encouraged to contact the PI or the IRB. Contact information will be provided in the consent forms 
including telephone, mail, and email. 

 
Page 13 of 20 
 
a. Sharing of Results with Subjects 
Data from this clinical trial will not be shared directly with participants. The results of the clinical trial 
and de-identified data will be made in accordance with NIH regulations and clinicaltrials.gov.  
 
b. Data and Specimen Banking 
No specimens will be stored. Study records will be retained for the longest regulatory retention period.  
After that time, records will be destroyed in a confidential manner.  
 
8. Data Analysis 
See Table 1 for outline of data analysis planned for study outcomes. As this is a pilot intervention trial, 
the focus will be on feasibility and acceptability of the pragmatic intervention trial. We will also explore 
effectiveness outcomes, but recognized we will be underpowered for a definitive effectiveness trial 
within this heterogeneous population selected to be representative of the population of interest. We 
will use our pilot trial to inform a future larger trial that will include longitudinal real world health 
outcomes relevant to the pediatric TBI population if supported by our preliminary results. 
Prior to evaluating outcomes, we will perform a thorough descriptive analysis of participant baseline 
characteristics (age, race, ethnicity, gender, pre-injury comorbidities, TBI characteristics including 
severity, location, and type). We will examine patterns of missingness in our outcomes collected at 1-
month, differences in participant and non-participant characteristics, and differences in participants 
who completed versus dropped out of the study to ascertain potential bias. Additionally, we will 
describe and compare the distribution of patient and clinical characteristics, including age and TBI 
severity, across treatment groups to ensure our randomization protocol was successful. Comparisons 
between groups will be made using chi-square tests for categorical variables. Depending on 
characteristics of the data, t-tests and Mann-Whitney U tests will be used to compare continuous 
variables between groups. We plan to perform both intention to treat and per protocol analyses.  
Quantitative feasibility outcomes will be presented as a percentage of patients, the denominators of 
which are listed in Table 1. Comparisons between groups will be made with chi-square tests. 
Quantitative acceptability outcomes for adverse events will be dichotomized to yes/no and evaluated as 
a total number for each patient summarized using percent and median with interquartile range (IQR), 
respectively. Acceptability outcomes for satisfaction will be measured using Likert scales for which we 
will present results as medians and IQR. Chi-square tests will be used to compare dichotomized 
outcomes between treatment groups, and Mann-Whitney U tests will be used to compare total number 
of events. Effectiveness outcomes will be summarized using means and standard deviations, except for 
daytime sleep episodes which will be summarized as a median and IQR; these outcomes will be 
summarized for the overall study population and by treatment group. We will primarily examine the 
effectiveness of our intervention using linear regression to assess differences in the total SDSC score 
across treatment groups at 1-month. Linear regression will allow us to assess differences in effectiveness 
outcomes while controlling for covariates that may confound this relationship; covariates of particular 
interest will include age and TBI characteristics. Covariates identified in our initial descriptive analysis as 
significantly different between treatment groups, and covariates significantly associated with SDSC total 
score in bivariate analyses will also be explored with multiple linear regression.  
Secondary effectiveness outcomes that specifically evaluate sleep phenotypes (measured by 
questionnaire and actigraphy) will be similarly evaluated with linear regression, except daytime sleep 
episodes which will be modeled using a count model, such as Poisson or negative binominal regression. 
For these secondary effectiveness outcomes, our focus is the magnitude of the association rather than 
statistical significance, as multiple comparisons will be made. Our primary goal with this secondary 
analysis will be to determine if the intervention appears effective for particular phenotypes that could 
be targeted in future studies. Results of these secondary analyses will be used as estimates for effect 
sizes in future intervention study design. 

 
Page 14 of 20 
 
Qualitative analysis of survey responses for feasibility and acceptability outcomes (Table 1) will be 
analyzed with thematic network analysis. Transcription of survey responses will be coded using a hybrid 
approach: 1)based on the pre-specified survey questions administered (deductive approach); 2)creating 
new codes as needed based on participant responses to open ended questions (inductive approach). 
Coded transcripts will be used to construct thematic networks identifying global and organizing themes 
reported among responses. Exploration and description of thematic networks will be used to identify 
patterns within data for interpretation. 
 
9. Privacy, Confidentiality, and Data Security 
Data and protected health information will be safeguarded in multiple ways. All data will be stored on and OHSU 
secure drive or in the OHSU secure REDCap database, which is encrypted, and password protected. Access to 
REDCap will be controlled by the PI and is stored on an OHSU encrypted and password protected server. All 
study forms will include only a study ID number. All study data will be inputted into REDCap by members of the 
study team trained in Human Subjects Research and Responsible Conduct of Research as well as study 
procedures.  The PI will maintain the REDCap database and provide access only to study team members.  All 
exports of data from REDCap will be coded. 
 
10. Provisions to Monitor the Data to Ensure the Safety of Subjects 
Adverse events related to the intervention trial will be assessed at hospital discharge, and at 30-days via 
clinic visit, survey, and medical record review. All adverse events will be recorded and reported as 
required.  
 
A Data and Safety Monitoring Plan (DSMP) including the provision of an institutional Data Safety 
Monitoring Board (DSMB) will be submitted as a separate documents for approval to the IRB.  
 
As this trial is a pilot investigation, we do not have prespecified stoppage criteria. Trial progress and 
safety will be closely monitored by the PI and DSMB. The PI will review Serious Adverse Events (SAEs) as 
they occur and the DSMB will review SAEs at each meeting and on an as-needed basis. The DSMB will 
review trial progress and safety. The DSMB recommendations may include study continuation without 
modification, study termination, study continuation with protocol modification, or temporary 
suspension of enrollment until further evaluation is completed. The DSMB will review each death 
occurrence. Cumulative SAEs for each study arm will be provided to the DSMB and reports will be 
submitted to the study team, IRB, program staff at the National Institutes of Health, and the Food and 
Drug Administration as required. If the PI is notified of any SAE that is thought possibly related to the 
study, the participant will be immediately withdrawn.  
 
11. Risks and Benefits 
a. Risks to Subjects 
Intervention risks will be considered more than minimal risk, but with potential to directly benefit the 
participant. Melatonin has demonstrated a good safety profile in multiple studies involving children and 
is available as a dietary supplement over the counter. A concern regarding use of over the counter 
melatonin is the variability in content and contaminants within supplements noted from lack of FDA 
oversight of dietary supplements.[87] We have minimized this risk by working with a manufacture that 
has provided Chemistry and Manufacturing Control data reviewed and approved for use by the FDA IND 
application. No serious adverse events have been reported with melatonin use in short or long-term 
studies as noted above. Studies using melatonin have reported symptoms including: dermatologic (itchy 
skin, rash), gastrointestinal (stomach upset, appetite changes, emesis), neurologic (drowsiness, blurred 
vision, vivid dreams), and bodily pain. Placebo studies report similar symptoms. Melatonin may affect 
levels of medications metabolized in the liver (particularly through CYP1A2 and CYP450 enzymes) or that 
are conjugated in the liver to sulfuric or glucuronic acid. There are unclear effects of melatonin on auto-

 
Page 15 of 20 
 
immune disorders and immune function. Melatonin is considered a dietary supplement, and as such, not 
regulated by the Food and Drug Administration. All risks will be communicated to the participant and 
included in the written consent provided to participants.  
No serious adverse events were reported in recent meta-analyses of studies using melatonin conducted 
in children with neurodevelopmental disorders, including epilepsy, or in a recent adult trial comparing 
melatonin and placebo, but melatonin appeared to effectively improve sleep. No serious adverse events 
were reported in a recent randomized trial in pediatric concussion using doses up to 10mg (double this 
trial’s maximum dosing).[76] The potential benefit of improved sleep after TBI in our study compared to 
the risk associated with melatonin is likely as favorable to standard care given >50% have disturbed 
sleep after discharge without treatment and SWD are associated with worse cognitive functions and 
quality of life in pediatric TBI patients.  
Given the ubiquitous use of melatonin in pediatric clinical care and research studies in a variety of 
pediatric populations with medical, developmental, and psychiatric disorders, no patients will be 
excluded for underlying medical conditions or concomitant medication use, outside of exclusion criteria 
above. Patients will be excluded from the trial if the clinical care Attending Physician deems the patient 
unable to tolerate enteral medications or otherwise has safety concerns regarding use of melatonin.  
There will be no requirement for use of contraception in female participants of child-bearing age given 
no known adverse effects of melatonin in pregnancy and short duration of the intervention. Pregnant 
patients will be excluded from the trial or withdrawn immediately from the trial if become pregnant. 
The educational intervention proposed in this study is of minimal risk given it is a handout with 
resources to promote healthy sleep. As part of our acceptability outcomes, we will evaluate utilization 
and usefulness of this portion of the intervention. 
Data collection, questionnaire and survey risks include loss of confidentiality. Participants will provide 
questionnaire and survey data via paper forms, electronic survey through REDCap, or telephone 
interview at 30-day time points.  Paper forms will only contain the subject study ID without other 
identifiable information to minimize risk of loss of privacy and confidentiality. Paper forms will be 
entered by a Research Assistant into REDCap. Access to identifiable information will be limited to study 
personnel and not shared with anyone outside the research group. Every effort will be made to 
minimize risk of loss of confidentiality. All study related paper forms will be destroyed after completion 
of the study. 
Actigraphy risks include loss of confidentiality and minor physical discomfort. Participants will wear 
actigraphy devices for a period of one month that pose no more than minimal risk to subjects.  
Actigraphy devices will be distributed to participants during clinical visits or via mail. System generated 
text messages are sent weekly to remind participants to sync with the smartphone app to collect 
actigraphy data. Participants will be consented for use of text messaging and can opt out at any time by 
contacting the research team. 
 
Study computers are password protected and encrypted within the OHSU network firewall and access 
will only be granted to study team members to minimize risk of loss of confidentiality.  Actigraphy 
devices are non-invasive and can be freely removed by participants, but there is a small risk of 
discomfort related to the device. Participants will be allowed to withdraw from this portion of the study 
if desired. 
 
b. Potential Benefits to Subjects 
Participants may directly benefit from the intervention given the high prevalence of sleep disturbances 
after TBI, and literature supporting melatonin and sleep educational interventions in pediatric 
populations with SWD targeting the most prevalent sleep problems seen after pediatric TBI. While the 
placebo arm may not benefit directly from intervention, the increased focus on sleep through 

 
Page 16 of 20 
 
recruitment into the trial may provide indirect benefit to all participants. There is a notable lack of 
interventions implemented in the hospital available to improve outcomes after pediatric TBI. SWDs 
represent a modifiable target associated with a variety of poorer post-discharge outcomes in pediatric 
TBI patients; thus, improving sleep may lead to improvement in multiple morbidities in pediatric TBI. 
 
12. Drugs or Devices  
 
The OHSU Research Pharmacy will oversee compounding and distribution of the study interventions 
(melatonin and placebo) per their standard operating procedures. 
 
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