Sleep in Pediatric Hematopoietic Stem Cell Transplant Patients
Phase: NA
Conditions: Sleep, Stem Cell Transplant Complications
Sponsor: Children's Hospital of Philadelphia

 
Template version: May 28, 2014 
 
Title: 
Sleep in Hematopoietic Stem Cell Transplant Patients 
Short Title 
Sleep in HSCT 
eIRB Number 
IRB 18-015878 
Protocol Date: 
1/29/2019 
Amendment 1 Date: 4/2/19 
 Amendment 5 Date: 5/28/2020 
Amendment 2 Date: 5/21/19 
Amendment 10 Date: 7/29/2020 
Amendment 3 Date:  9/2/19 
Amendment 14 Date 3/12/2021  
Amendment 4 Date: 1/10/2020 
Amendment 15 Date: 8/2/21 
Amendment 16 Date 3/14/22 
 
Study Principal Investigator: Lamia Barakat, Ph.D.  
The Children’s Hospital of Philadelphia 
3501 Civic Center Blvd., 10303 CTRB 
Philadelphia PA 19104 
Phone 267-426-8135 
email: barakat@email.chop.edu 
 
 

  
 
 
 
 
 
 
 
ii
TABLE OF CONTENTS 
Table of Contents ................................................................................................................... ii 
Abbreviations and Definitions of Terms ............................................................................. iv 
Abstract .................................................................................................................................. v 
Table 1: Schedule of Study Procedures .............................................................................. vi 
Figure 1: Study Diagram ..................................................................................................... vii 
1 
BACKGROUND INFORMATION AND RATIONALE ....................................................................... 1 
1.1 
INTRODUCTION ..................................................................................................................................... 1 
1.2 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT OR INTERVENTION ..................................... 1 
1.3 
FINDINGS FROM NON-CLINICAL AND CLINICAL STUDIES ............. ERROR! BOOKMARK NOT DEFINED. 
1.4 
SELECTION OF DRUGS AND DOSAGES ........................................... ERROR! BOOKMARK NOT DEFINED. 
1.5 
RELEVANT LITERATURE AND DATA ..................................................................................................... 1 
1.6 
COMPLIANCE STATEMENT .................................................................................................................... 3 
2 
STUDY OBJECTIVES .............................................................................................................................. 3 
2.1 
PRIMARY OBJECTIVE (OR AIM) ............................................................................................................ 3 
2.2 
SECONDARY OBJECTIVES (OR AIM) ...................................................................................................... 3 
3 
INVESTIGATIONAL PLAN .................................................................................................................... 3 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ................................................................................................. 3 
3.1.1 
Screening Phase .............................................................................................................................. 4 
3.1.2 
Study Treatment Phase (start of the study intervention) ................................................................. 4 
3.1.3 
Phase 2 ............................................................................................................................................ 4 
3.2 
ALLOCATION TO TREATMENT GROUPS AND BLINDING ........................................................................ 5 
3.3 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES ................................................................... 5 
3.3.1 
Duration of Study Participation ...................................................................................................... 5 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected .................................................. 5 
3.4 
STUDY POPULATION ............................................................................................................................. 5 
3.4.1 
Inclusion Criteria ............................................................................................................................ 5 
3.4.2 
Exclusion Criteria ........................................................................................................................... 5 
4 
STUDY PROCEDURES ............................................................................................................................ 6 
4.1 
SCREENING VISIT ................................................................................................................................. 6 
• 
PATIENTS AND FAMILIES WILL BE PRESENTED THE STUDY ON FAMILY EDCATION DAY PRIOR TO 
ADMISSION FOR HSCT ...................................................................................................................................... 6 
4.2 
STUDY TREATMENT PHASE .................................................................................................................. 6 
4.2.1 
Visit 1 Day -2 to Day -1 before transplant ...................................................................................... 6 
4.2.2 
Visit 2 Day 0 .................................................................................................................................... 6 
4.2.3 
Visit 3 Day +4 ................................................................................................................................. 6 
4.2.4 
Visit 4 Day +10 ............................................................................................................................... 6 
4.2.5 
Visit 5 Day +15 ............................................................................................................................... 6 
4.3 
UNSCHEDULED VISITS .......................................................................................................................... 7 
4.4 
CONCOMITANT MEDICATION ....................................................... ERROR! BOOKMARK NOT DEFINED. 
4.5 
RESCUE MEDICATION ADMINISTRATION ...................................... ERROR! BOOKMARK NOT DEFINED. 
4.6 
SUBJECT COMPLETION/WITHDRAWAL ................................................................................................. 7 
4.6.1 
Early Termination Study Visit ......................................................................................................... 7 
5 
STUDY EVALUATIONS AND MEASUREMENTS .............................................................................. 8 
5.1 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS .................................................. 8 
5.1.1 
Medical Record Review ................................................................................................................... 8 
5.1.2 
Physical Examination ...................................................................... Error! Bookmark not defined. 
5.1.3 
Vital Signs ....................................................................................... Error! Bookmark not defined. 

 
 
 
 
 
 
 
 
iii 
5.1.4 
Laboratory Evaluations................................................................... Error! Bookmark not defined. 
5.1.5 
Other Evaluations, Measures .......................................................................................................... 8 
5.2 
EFFICACY EVALUATIONS ..................................................................................................................... 9 
5.2.1 
Diagnostic Tests, Scales, Measures, etc. ......................................................................................... 9 
5.3 
PHARMACOKINETIC EVALUATION ................................................ ERROR! BOOKMARK NOT DEFINED. 
5.4 
SAFETY EVALUATION ........................................................................................................................... 9 
6 
STATISTICAL CONSIDERATIONS ...................................................................................................... 9 
6.1 
PRIMARY ENDPOINT ............................................................................................................................. 9 
6.2 
SECONDARY ENDPOINTS .................................................................................................................... 10 
6.3 
STATISTICAL METHODS ...................................................................................................................... 10 
6.3.1 
Baseline Data ................................................................................................................................ 10 
6.3.2 
Efficacy Analysis ........................................................................................................................... 10 
6.3.3 
Pharmacokinetic Analysis ............................................................... Error! Bookmark not defined. 
6.3.4 
Safety Analysis .............................................................................................................................. 10 
6.4 
SAMPLE SIZE AND POWER .................................................................................................................. 10 
6.5 
INTERIM ANALYSIS ...................................................................... ERROR! BOOKMARK NOT DEFINED. 
7 
STUDY INTERVENTION ...................................................................................................................... 11 
7.1 
DESCRIPTION ...................................................................................................................................... 11 
8 
SAFETY MANAGEMENT ..................................................................................................................... 11 
8.1 
CLINICAL ADVERSE EVENTS .............................................................................................................. 11 
8.2 
ADVERSE EVENT REPORTING ............................................................................................................. 11 
9 
STUDY ADMINISTRATION ................................................................................................................. 11 
9.1 
TREATMENT ASSIGNMENT METHODS ................................................................................................. 11 
9.1.1 
Randomization............................................................................................................................... 11 
9.1.2 
Blinding ........................................................................................... Error! Bookmark not defined. 
9.1.3 
Unblinding ...................................................................................... Error! Bookmark not defined. 
9.2 
DATA COLLECTION AND MANAGEMENT ............................................................................................ 11 
9.3 
CONFIDENTIALITY .............................................................................................................................. 13 
9.4 
REGULATORY AND ETHICAL CONSIDERATIONS .................................................................................. 13 
9.4.1 
Data and Safety Monitoring Plan ................................................................................................. 13 
9.4.2 
Risk Assessment ............................................................................................................................. 13 
9.4.3 
Potential Benefits of Trial Participation ....................................................................................... 13 
9.4.4 
Risk-Benefit Assessment ................................................................................................................ 14 
9.5 
RECRUITMENT STRATEGY .................................................................................................................. 14 
9.6 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ............................................................ 14 
9.6.1 
Waiver of Consent ........................................................................... Error! Bookmark not defined. 
9.6.2 
Waiver of Assent .............................................................................. Error! Bookmark not defined. 
9.6.3 
Waiver of HIPAA Authorization ...................................................... Error! Bookmark not defined. 
9.7 
PAYMENT TO SUBJECTS/FAMILIES ...................................................................................................... 15 
9.7.1 
Reimbursement for travel, parking and meals ................................ Error! Bookmark not defined. 
9.7.2 
Payments to parent for time and inconvenience (i.e. compensation) ............ Error! Bookmark not 
defined. 
9.7.3 
Payments to subject for time, effort and inconvenience (i.e. compensation) ................................. 15 
9.7.4 
Gifts ................................................................................................. Error! Bookmark not defined. 
10 
PUBLICATION ........................................................................................................................................ 15 
11 
REFERENCES ......................................................................................................................................... 15 
Appendix ............................................................................................................................... 18 
 

  
 
 
 
 
 
 
 
iv
ABBREVIATIONS AND DEFINITIONS OF TERMS 
HSCT 
 
Hematopoietic stem cell transplant 
HRQL 
 
Health-related quality of life 
AE 
 
Adverse event 
EHR 
MRN 
                    
 
Electronic Health Record 
Medical Record Number 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
 
 
 
 
 
 
 
v
ABSTRACT 
Context:  Patients undergoing treatment for cancer face disease, treatment, and 
environmental obstacles to sufficient, sound sleep1. Hospitalizations can further worsen 
sleep quality and quantity due to overnight vitals checks, medication administration, blood 
draws, and environmental noise and light2. For patients undergoing hematopoietic stem cell 
transplant (HSCT), the risk for poor sleep is especially high due to protracted 
hospitalization, frequent vitals checks resulting in multiple night awakenings3, and high 
symptom burden peaking approximately 10 days post-transplant4.  
Objectives:  
Primary: Test the acceptability and feasibility of protecting one 6-hour window for 
nighttime sleep (intervention) relative to regular vitals checks (observation only periods) 
during HSCT recovery. 
Secondary: Assess the effect of one 6-hour window for nighttime sleep on subject sleep and 
engagement in supportive care on the HSCT unit.  
Study Design:  
Aggregated N=1 randomized controlled design. All participants will undergo a 5 day 
observation and then be randomized to receive the 5 day intervention (extended vitals 
checks) during either nights of days +5-+9 or days +10-+14.   
Setting/Participants: 
Inpatients on the HSCT Unit at CHOP 
Study Interventions and Measures:  
Intervention—increasing time between vitals checks from every 4 hours to one 6-hour 
period at night. 
Subjects will wear an actigraph for the duration of the study, complete a daily sleep diary, 
and complete self- and parent-proxy psychosocial measures (symptom burden, health 
related quality of life, sleep) and acceptability. Medical record review will also be 
conducted to assess vitals check frequency. 

 
vi  
 
 
 
 
 
 
 
TABLE 1: SCHEDULE OF STUDY PROCEDURES  
Visit 
Purpose 
Main Procedures 
Duration 
Visit 1                
Pre-transplant 
Baseline 
measures  
Complete Informed consent 
Complete CEFIS 
Complete self-report measures 
Give actigraph 
35 minutes 
Visit 2,    
Transplant Day 0 
Start actigraph 
Review actigraphy procedures 
5 minutes 
Visit 3,    
Transplant Day +5 
Randomization 
Randomize to intervention start 
Complete self-report measures 
20 minutes 
Visit 4,    
Transplant Day +10 
Psychosocial 
measures 
Complete self-report measures 
15 minutes 
Visit 5,    
Transplant Day +15 
End of Study 
Return actigraph, Complete self-report 
measures including acceptability measure 
20 minutes 
.

 
page vii 
  
 
 
 
FIGURE 1: STUDY DIAGRAM 
 
 
*Each study period will include nights and symptom burden and sleep will be collected the day 
following the end of the study period.  For example, sleep from night +4 and symptom burden 
for the day 0-+4 period will be collected on day +5.  
 
Intervention 
Observation 
Intervention 
Randomize day +5 
Study Day 1-5 
Day 6-10
Day 11-15
Observation 
Observation 
Day from transplant 
0-+4* 
Day from transplant
+5-9*
Day from transplant  
+10-14*

 
  
 
 
 
1
1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 Introduction 
Patients undergoing treatment for cancer face disease, treatment, and environmental obstacles 
to sufficient, sound sleep1. Hospitalizations can further worsen sleep quality and quantity due 
to overnight vitals checks, medication administration, blood draws, and environmental noise 
and light2. For patients undergoing HSCT, the risk of poor sleep is especially high due to 
protracted hospitalization, frequent vitals checks resulting in multiple night awakenings3, and 
high symptom burden peaking approximately 10 days post-transplant4. Sleep quality and 
quantity is associated with immune functioning5, wound healing6, and resistance to infection7, 
all critical to physical recovery from cancer and cancer treatments. Poor sleep may also have 
a psychosocial impact by limiting engagement in supportive care (PT/OT/School/Creative 
Arts Therapy/Psychology) due to compensatory daytime sleep and fatigue8. Together the 
physical impact of poor sleep and limited engagement in supportive care may hinder HSCT 
recovery. Frequent vitals checks are one potential intervention target when seeking to improve 
sleep. Vitals checks every 4 hours are necessary during conditioning and immediately post-
transplant, but for many patients extending the time between vitals checks is possible. 
Through an aggregated N=1 randomized controlled design (each patient will serve as their 
own control, with the timing of the 5-day intervention period determined by randomization), 
the current study will test acceptability, feasibility, and impact on sleep and supportive care 
engagement of protecting one 6-hour window for nighttime sleep (intervention) relative to 
regular vitals checks (observation) during HSCT recovery. 
1.2 Name and Description of Investigational Product or Intervention 
The intervention tested is protecting one 6-hour window for nighttime sleep (intervention) 
relative to regular vitals checks (observation) during HSCT recovery. 
1.3 Relevant Literature and Data 
Sleep disturbances are common in pediatric oncology. Sleep disturbances frequently occur 
across the continuum of cancer treatment into survivorship9. Sleep is an understudied area of 
health-related quality of life10 (HRQL) that can significantly impact cognitive functioning11, 
behavior12, mood13, academic progress13, and parental and family functioning14. Sleep quality 
and quantity is also associated with immune functioning5, wound healing6, and resistance to 
infection7, all critical to physical recovery from cancer and cancer treatments. Thus, sleep is 
a logical and important target of assessment and intervention to improve HRQL and health 
outcomes for individuals—especially children receiving treatment for cancer. 
Sleep is central to the experience of cancer-related symptoms. Disrupted sleep can 
exacerbate the physiological processes of pain15 and fatigue16. Psychologically, poor sleep 
impacts cognitive appraisals of symptoms and symptom-related coping efforts the following 
day, which may amplify the patient’s experience of symptoms17. Symptoms may then interfere 
with sleep the following night resulting in a vicious cycle between sleep and symptoms that 
can be difficult to stop. In pediatric cancer, sleep disturbances are closely related to general 
symptom burden. Pediatric cancer patients report between 6 (outpatient) and 12 (inpatient) 
symptoms that co-occur during cancer treatment, with prevalence rates of fatigue, insomnia, 
pain, and psychological symptoms ranging from 30-50%18. Studies describing the symptom 

 
  
 
 
 
2
cluster of sleep disturbances, fatigue, and pain indicate that fatigue and sleep predict 
depression and behavior changes in adolescents but not younger patients19, suggesting a 
developmental component unique to older pediatric patients in the response to cancer and its 
treatment. Disturbed sleep may precipitate symptoms or be the result of higher symptom 
burden, potentially exacerbating symptoms over time.   
The hospital environment is extremely disruptive to sleep. Patients undergoing treatment 
for cancer face disease, treatment, and hospital environmental obstacles to sufficient, sound 
nighttime sleep1. Hospitalizations can further worsen sleep quality and quantity due to 
overnight vitals checks, medication administration, blood draws, and environmental noise and 
light2. For patients undergoing hematopoietic stem cell transplant (HSCT), the risk for poor 
sleep is especially high due to the protracted hospitalization, frequent vitals checks resulting 
in multiple night awakenings3, and high symptom burden peaking approximately 10 days 
post-transplant4.  
Limited research has examined sleep in pediatric HSCT patients. Sleep, as measured by 
one global question about sleep quality, worsens from 1-week pre-transplant through 3-weeks 
post-transplant before improving20. To our knowledge only one study has focused on sleep in 
pediatric HSCT patients using objective measurement (actigraphy) in 8 children; results 
indicated patients awaken 12 times per night on average and hospital rooms were entered 
approximately the same number of times3, suggesting that hospital staff play a role in sleep 
disruption. In adults, 77% of patients undergoing HSCT report clinically significant poor 
sleep, and that poor sleep is related to increased fatigue and decreased physical functioning 
during the hospitalization21 while good sleep quality is related to better pre/post HSCT 
monocytic chemokines, biomarkers indicating immune recovery22. Sleep improves post-
transplant; however, at day 100+ 28% of adult patients still report clinically significant sleep 
disturbances21.  
Interventions to promote sleep and physical activity have been piloted in pediatric 
oncology, but they are often not sustainable outside of research. Hospital-based 
interventions that seek to provide education about sleep and fatigue management23, encourage 
physical activity24, and protect 90-minute windows for sleep25 have been tested in small pilot 
studies in oncology.  Generally, families report interventions to be acceptable, but many 
interventions are not clinically feasible, requiring substantial support to continue outside of 
the context of research. Scalable interventions that can be integrated into clinical practice are 
needed to improve the psychosocial health of patients during hospitalizations.   
The contribution of staff room entries to poor sleep3 is a logical intervention target. 
Frequent vitals checks are necessary early in the transplant process but become less necessary 
post-transplant, thus extending time between vitals checks is likely feasible and has the 
potential to increase total sleep time. By altering hospital procedures to maximize sleep, we 
have the opportunity to address hospital-related sleep disruptions and improve outcomes in 
patients in need of sufficient sleep—patients recovering from HSCT. It is hypothesized that 
patients who obtain uninterupted sleep would perhaps participate more in therapies (PT/OT) 
to regain physical stamina, school activities, creative art therapy, and psychological services 
to continue cognitive recovery and bolster HRQL. Taken in sum, it is hypothesized that more 
sleep and increased participation in these activities would ultimately accelerate their recovery 
and physical functioning. 

 
  
 
 
 
3
1.4 Compliance Statement 
This study will be conducted in full accordance all applicable Children’s Hospital of 
Philadelphia Research Policies and Procedures and all applicable Federal and state laws and 
regulations including 45 CFR 46. All episodes of noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain 
consent and assent, and will report unanticipated problems involving risks to subjects or 
others in accordance with The Children’s Hospital of Philadelphia IRB Policies and 
Procedures and all federal requirements. Collection, recording, and reporting of data will be 
accurate and will ensure the privacy, health, and welfare of research subjects during and 
after the study.  
2 
STUDY OBJECTIVES 
The purpose of the study is to assess the acceptability and feasibility of a novel intervention 
to improve sleep in the hospital setting, which will provide evidence for a clinical 
intervention that can improve patient functioning during hospitalizations.  
2.1 Primary Objective (or Aim) 
The primary aim of the study is to assess the feasibility and acceptability of increasing time 
between vitals checks in HSCT. 
2.2 Secondary Objectives (or Aim) 
The secondary objectives are to: 
Test the relationship between increasing time between vital checks and sleep. 
Compare engagement in supportive care interventions (PT/OT/School/Creative Arts 
Therapy/Psychology), HRQL, and symptom burden between observation and intervention 
periods. 
3 
INVESTIGATIONAL PLAN 
3.1 General Schema of Study Design 
Patients undergoing HSCT face many challenges to restful sleep during the hospitalization 
for transplant. Frequent vitals checks, necessary during conditioning and immediately post-
transplant, may be less necessary as time from transplant increases. Utilizing an aggregated 
N=1 randomized trial design (Figure 1. Study Flow), the current study will test protecting 
one 6-hour window for sleep within patients recovering from HSCT. This study will assess 
the acceptability and feasibility of this intervention, evaluate the impact on patient sleep, and 
test how sleep is related to symptom burden, engagement in supportive services, and HRQL 
during HSCT recovery. Participants will wear an actigraph for the duration of the study (day 
of the transplant [day 0] through the night of Day +14post-transplant, removing the 
actigraph upon awakening on Day +15) to measure sleep accompanied by a brief sleep diary 
sent daily by text messages delivered via REDCap and its integration with Twilio.  
Participants will complete self-report measures of sleep, symptom burden, and HSCT related 

 
  
 
 
 
4
HRQL at baseline and at the end of each study period (Day +5, +10, +15; Table 1 Study 
Procedures).   
3.1.1 Screening Phase 
Potential subjects will be identified through the Stem Cell Transplant List using inclusion 
criteria for enrollment: ages 8-21, receiving HSCT at CHOP, English speaking, with no 
history of developmental delays. Subjects will be recruited into two strata, children ages 8-
12 years and adolescents and young adults ages 13-21 years.  
Parental/guardian permission (informed consent) and, if applicable, child assent, will be 
obtained prior to any study-related procedures being performed. Eligibility criteria will be 
confirmed by the subject’s oncologist.  Participants will be approached about study 
participation on transplant education day or during the conditioning admission, if interested 
the study team will follow up with the family 1-2 days before the transplant to complete the 
informed consent process and the baseline measures.   
3.1.2 Study Treatment Phase (start of the study intervention) 
One-two days before the transplant, a study team member will meet with the family to 
complete the informed consent, baseline measures, and give actigraphy instructions. All 
patients will wear an actigraph from the day of the transplant until day +5 from the transplant 
to serve as the “observation baseline” for each patient. 
3.1.3 Phase 2  
On Day +5, to reduce the impact of expectancies during the first observation period, patients 
will be randomized to ABA (observation/intervention/observation) or AAB 
(observation/observation/intervention), with each period lasting 5 days (Fig. 1). Block 
randomization stratified by age will be used to ensure similar age distribution between 
groups. The two group design will allow for the comparison of altering vitals checks 
before/after engraftment and peak symptom burden (typically on day +104). On each 
intervention night, the research team will verify with the child’s provider that it is acceptable 
for the patient to have a 6-hour window between vitals checks. This confirmation will be 
communicated to the child’s nighttime nurse. For the 5 days of the child’s intervention 
period, the nurse will be instructed to conduct the last vitals check between 9pm-1am. After 
the last vitals check, the patient will be given 6 hours until the next vitals check, unless the 
caregiver/patient request nursing. Patients will continue to wear the actigraph until the end 
of the study. The patient can remove the actigraph upon awakening on Day +15. 
Eligibility for extended vitals check, assessed daily: 1) No fever in the last 24 hours; 2) No 
concurrent chemotherapy administration; 3) No ongoing or active infection; and 4) No organ 
toxicity requiring labs more than every 6 hours. Even if a patient is ineligible for extended 
vitals checks they are asked to continue to wear the actigraph.  
After each patient has completed both the intervention and a second observation (either BA 
or AB), they will be asked to complete final study measures and measures of acceptability of 
the intervention.   

 
  
 
 
 
5
3.2 Allocation to Treatment Groups and Blinding 
Participants will be randomized to either Observation/Intervention or 
Intervention/Observation on day +5 post-transplant. The research coordinator will generate a 
randomization sequence using a random number generator, with block randomization 
occurring based on participant age (8-12 or 13-21).  Blinding will not be possible, but 
randomization will occur on day +5 to minimize the impact of the intervention on the initial 
observation period.  
3.3 Study Duration, Enrollment and Number of Sites 
3.3.1 Duration of Study Participation 
The study duration per subject will be up to approximately 17 days, from the beginning of 
data collection (the day before the transplant), up to 5 days Phase 1 and up to 10 days Phase 
2. 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will only be conducted at The Children’s Hospital of Philadelphia.   
Recruitment will stop when approximately 55 subjects and their parent caregivers are 
enrolled.  It is expected that approximately 55 subjects will be enrolled to produce 50 
evaluable subjects. Subject nurses will also be enrolled, it is expected that each subject may 
have between 1 and 5 nurses involved in care during the extended vitals check period, 
Because some nurses will likely provide care to multiple patients, we expect to enroll 75 
nurses. 
3.4 Study Population 
3.4.1 Inclusion Criteria  
(Patient Subjects)  
1) Males or females age 8 to 21 years.   
2) Undergoing HSCT at The Children’s Hospital of Philadelphia  
3) Parent/guardian permission (informed consent) and if appropriate, child assent. 
(Nurse Subjects) 
4) HSCT Nurse working night shift during subject’s extended vitals check. 
3.4.2 Exclusion Criteria 
1) History of developmental delays given the relationship to sleep/wake patterns 
2) Sleep disorder diagnosis as documented in the medical record 
3) Cognitive delays that impact the ability to complete study measures 
4) Not proficient in English 

 
  
 
 
 
6
Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations 
of these criteria must be reported in accordance with IRB Policies and Procedures.  
4 
STUDY PROCEDURES 
4.1 Screening Visit 
• Patients and families will be presented the study on Family Edcation Day prior to 
admission for HSCT 
4.2 Study Treatment Phase 
General overview of this phase.  
4.2.1 Visit 1 Day -2 to Day -1 before transplant  
• Informed Consent 
• Medical Record Review 
• Demographic, COVID-19 Impact measure, and Psychosocial Measures (Symptom 
Burden, HRQL, and Sleep) 
• Introduce actigraph and electronic sleep diary. 
4.2.2 Visit 2 Day 0 
• Place actigraph on patient’s non-dominant wrist. Patient is asked to wear the 
actigraph for the duration of the study (morning of Day 0- the night of Day +14). The 
patient can remove the actigraph upon awakening on Day +15.  
• Review actigraph and electronic sleep diary procedures. 
4.2.3 Visit 3 Day +5 
• Randomization 
• Psychosocial Measures (Symptom Burden, HRQL, and Sleep) 
4.2.4 Visit 4 Day +10 
• Psychosocial Measures 
4.2.5 Visit 5 Day +15 
• Psychosocial Measures 
• Return Actigraph 
• Acceptability survey 
• Subject payment 

 
  
 
 
 
7
4.2.6 Nurse Study Proecdure 
Visit 1  Morning after patient completes extended vitals check night  
Informed Consent, will take place either by phone or on the HSCT Unit with study 
staff 
Acceptability Survey 
4.3 Unscheduled Visits 
Subjects will be hospitalized for the duration of the study.  Should the family or the 
treatment team have concerns about the subject’s participation or study procedures, the 
study team will meet with the patient to discuss whether the family would like to remain in 
the study.  
4.4 Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to their care.  They 
may also be discontinued from the study at the discretion of the Investigator for lack of 
adherence to study treatment or visit schedules, AEs, or due to a change in medical status.  
The Investigators may also withdraw subjects who violate the study plan, or to protect the 
subject for reasons of safety or for administrative reasons.  It will be documented whether or 
not each subject completes the clinical study. If the Investigators become aware of any 
serious, related adverse events after the subject completes or withdraws from the study, they 
will be recorded in the source documents and on the CRF. 
4.4.1 Early Termination Study Visit 
Subjects who withdraw from the study will be asked to return the actigraph and complete the 
acceptability measure.  

 
  
 
 
 
8
5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 Screening and Monitoring Evaluations and Measurements 
5.1.1 Medical Record Review 
Include a listing of the variables that will be abstracted from the medical chart (paper or 
electronic). 
• Date of birth 
• Date of diagnosis and treatment history  
• Medications 
• Length of hospitalization prior to starting the study 
• Number of visits completed or declined with supportive services (physical therapy, 
occupational therapy, school, creative arts therapies, and/or psychology) for each 
study period (Days 0-+4 including nights, Days +5-+9 including nights, Days +10-
+14 including nights). 
• Frequency and timing of vitals checks for each day in the study.  
• Medications used for supportive care for each study period (Days 0-+4 including 
nights, Days +5-+9 including nights, Days +10-+14). 
• Transplant parameters including: type of transplant, disease status, cell processing, 
GVHD prophylaxis and infectionus prophylaxis.    
5.1.2 Other Evaluations, Measures 
Subjects and caregivers will complete the following measures: 
Table 1. Study Measures. 
Baseline Day 
+5 
Day 
+10 
Day 
+15 
Construct 
Measure 
Acceptability Patient, caregiver, and nurse will respond to 
a brief questionnaire of acceptability of 
adjusting vitals checks. 
 
 
 
x 
Demographics Report of sex, race/ethnicity, age of child and 
caregiver 
x 
 
 
 
COVID-19 
Impact 
COVID-19 Exposure and Family Impact 
Survey (CEFIS) to assess family exposure 
to and experience with COVID-19 through 
Yes/No responses (25 items); 12 items 
assessing the impact of the pandemic on 
x 
 
 
 

 
  
 
 
 
9
self/family with 1-4 intensity scale and 1 
open-ended item 
HRQL and 
related 
symptoms 
Pediatric Quality of Life Inventory—Stem 
Cell Transplant Module. This measure 
assesses HRQL and syptoms relevant to 
patients undergoing HSCT. The measure 
includes questions about pain, 
fatigue/sleep, nausea, communication, 
worry, nutrition, thinking and other 
symptoms answered on parallel child and 
adolescent with parent proxy forms (41 
items).26 
x 
x 
x 
x  
Sleep 
PROMIS Sleep Measures—Sleep 
disturbance, sleep-related impairment, and 
sleep hygiene over the past week-parallel 
parent/child forms (24 items)27.  
x 
x 
x 
x 
Supportive 
Care Use 
EHR review to document engagement or 
refusal of PT/OT/School/Creative Art 
Therapy/ Psychology for each 5 day period. 
 
x 
x 
x  
Actigraphy 
Worn by participant day 0-night of Day +14, removing on awakening on 
Day+15. To validate actigraphy: bedtime, waketime, night awakenings, 
naps, time actigraph was off reported daily through text messages delivered 
via REDCap and its integration with Twilio. 
 
5.2 Efficacy Evaluations 
5.2.1 Diagnostic Tests, Scales, Measures, etc. 
Actigraphy will be used to track the impact of extending vitals check on sleep. 
5.3 Safety Evaluation 
Subject safety will be monitored by adverse events, study visits, and daily checks with the 
subject’s treatment team during the intervention (i.e., extended vitals checks) period. 
6 
STATISTICAL CONSIDERATIONS 
6.1 Primary Endpoint 
The primary endpoint is the acceptability and feasibility of the intervention.  Acceptability 
will be measured by subjects, caregivers, and nursing ratings of the intervention.  Feasibility 
will be measured through study staff documented medical eligibility to participate in the 
intervention each eligible day and by tracking compliance with extended vitals checks, 
through electronic health record (EHR) review. 

 
  
 
 
 
10 
6.2 Secondary Endpoints 
Secondary endpoints will include the following: 
• The change in sleep between observation and intervention period as measured by 
actigraphy sleep efficiency, total sleep time, and number of awakenings. 
• The change in engagement in supportive services between observation and intervention 
period (physical therapy, occupational therapy, school and/or psychology) as measured 
through EHR review.   
6.3 Statistical Methods 
6.3.1 Baseline Data  
Baseline and demographic characteristics will be summarized by standard descriptive 
summaries (e.g. means and standard deviations for continuous variables such as age and 
percentages for categorical variables such as gender). 
6.3.2 Efficacy Analysis 
Using descriptive statistics, feasibility will be determined by assessing medical eligibility for 
the intervention and the delivery of the intervention. Descriptive statistics will be used to 
characterize acceptability measure responses  
Secondary endpoints will include the change in sleep parameters and engagement in 
supportive care services. We will utilize hierarchical multilevel mixed-effects models for daily 
diary data, which uses all available data, allows for multilevel nesting (e.g., daily data nested 
within participants, nested within condition), and are fairly robust to missing data (models are 
valid under Missing At Random assumption)28. Fixed and random effects models will be fit 
to the data29 to estimate the impact of the intervention on nocturnal sleep (sleep efficiency, 
total sleep time, night awakenings); Aim 2) and engagement in supportive care, HRQL, and 
symptom burden (Aim 3). We will test for carryover effects of the intervention and adjust 
analyses as needed29.  
6.3.3 Safety Analysis 
AE incidence will be summarized along with the corresponding exact binomial 95% two-
sided confidence intervals. 
6.4 Sample Size and Power 
The current study is a pilot that is seeking to test the acceptability and feasibility of an 
intervention to increase sleep during HSCT.  16 subjects will yield an adequate sample size 
for a pilot study30 to estimate effect sizes for a future trial. 
 

 
  
 
 
 
11 
7 
STUDY INTERVENTION 
7.1 Description 
For the 5 day-intervention period, the study staff will work with the subject’s nurse to 
plan on 6-hour extended period between vitals checks, occurring overnight.  On each 
intervention night, the research team will verify with the child’s oncology provider that 
it is acceptable for the patient to have a 6-hour window between vitals checks. This 
confirmation will be communicated to the child’s nighttime nurse. For the 5 days of the 
child’s intervention period, the nurse will be instructed to conduct the last vitals check 
between 9pm-1am. After the last vitals check, the patient will be given 6 hours until the 
next vitals check, unless the caregiver/patient request nursing.  
8 
SAFETY MANAGEMENT 
8.1 Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  
8.2 Adverse Event Reporting 
Since the study procedures are not greater than minimal risk, SAEs are not expected. If any 
unanticipated problems related to the research involving risks to subjects or others happen 
during the course of this study (including SAEs) they will be reported to the IRB in 
accordance with CHOP IRB SOP 408: Unanticipated Problems Involving Risks to Subjects. 
AEs that are not serious but that are notable and could involve risks to subjects will be 
summarized in narrative or other format and submitted to the IRB at the time of continuing 
review.  
9 
STUDY ADMINISTRATION 
9.1 Treatment Assignment Methods 
9.1.1 Randomization 
Participants will be randomized to either Observation/Intervention or 
Intervention/Observation on day +5 post-transplant. The research coordinator will generate a 
randomization sequence using a random number generator, with block randomization 
occurring based on participant age (8-12 or 13-21).  Blinding will not be possible, but 
randomization will occur on day +5 to minimize the impact of the intervention on the initial 
observation period.  
9.2 Data Collection and Management 
Electronic health record data.  
Investigators will generate a list of MRNs for participants with positive parental consent 
who have completed the survey.  A trained research assistant with limited EHR access will 
extract treatment related data from the EHR. To obtain a password for the EHRs, all staff 
must complete training on the importance of patient privacy. Training on the Health 
Insurance Portability and Accountability Act (HIPAA) is required for all employees. With 
the EHRs, patient privacy is protected by multi-step, system wide processes. Anyone 

 
  
 
 
 
12 
wishing to view the charts of patients for whom they do not provide care must “break the 
glass.” This system requires a declaration of why the chart is being viewed and sends a 
message to both an employee’s supervisor and the hospital’s privacy officer. In summary, 
the inappropriate access to electronic health information is carefully monitored and strictly 
prohibited. All study files retained on CHOP’s secure network or within secure REDCap 
database will be accessed only by study staff using a CHOP issued, password-protected 
computer.   
 
Child- and parent-report data: 
Participants will complete daily sleep diary questions using REDCap and the integration 
with Twilio (a text messaging platform that integrates with REDCap). No PHI will be 
transmitted over text message. Electronic demographic, psychosocial, and acceptability 
surveys will also be obtained using REDCap. The CHOP Research Institute Center for 
Biomedical Informatics (CBMi) will be used as a central location for data processing and 
management. These data will be stored within REDCap by participant study ID.  
 
Nurse acceptability data: 
Nurses will complete acceptability questionnaires for each night they care for the child 
during the extended vitals check portion of the study using REDCap and the integration with 
Twilio (a text messaging platform that integrates with REDCap). No PHI will be transmitted 
over text message. The CHOP Research Institute Center for Biomedical Informatics (CBMi) 
will be used as a central location for data processing and management. These data will be 
stored within REDCap by participant study ID. 
 
Confidentiality of On-Line Assessment.  
Participants will complete self-report questionnaires through internet access to REDCap. 
Daily text messages will be completed and stored within REDcap via the integration with the 
text messaging platform Twilio. No PHI will be transmitted over text message. Participants 
will complete questionnaires that are only identified with a unique Study ID, which will be 
assigned during recruitment. The CHOP Research Institute Center for Biomedical Informatics 
(CBMi) will be used as a central location for data processing and management. CBMi 
represents CHOP in a consortium of over three hundred academic research institutions led by 
Vanderbilt University. Vanderbilt, with assistance from the consortium, has developed a 
software toolset and workflow methodology for electronic collection and management of 
research and clinical trial data. REDCap (Research Electronic Data Capture) data collection 
projects rely on a thorough study-specific data dictionary defined in an iterative self-
documenting process by all members of the research team with planning assistance from 
CBMi. The iterative development and testing process results in a well-planned data collection 
strategy for individual studies. REDCap is also a powerful tool for building and managing 
online surveys. The research team can create and design surveys in a web browser and engage 
potential respondents using a variety of notification methods. REDCap provides secure, web-
based applications that are flexible enough to be used for a variety of types of research, provide 
an intuitive interface for users to enter data and have real time validation rules (with automated 
data type and range checks) at the time of entry. These systems offer easy data manipulation 
with audit trails for reporting, monitoring, and querying patient records, and an automated 

 
  
 
 
 
13 
export mechanism to common statistical packages (SPSS, SAS, Stata, R/S-Plus). Within 
REDCap, all data are stored by study ID number only.   
 
9.3 Confidentiality 
No identifiable data will be used for future study without first obtaining IRB approval. The 
investigator will obtain a data use agreement between the provider (the PI) of the data and 
any recipient researchers (including others at CHOP and Rutgers University) before sharing 
a de-identified data set (all dates and zipcodes will be removed).   
9.4 Regulatory and Ethical Considerations 
9.4.1 Data and Safety Monitoring Plan 
An independent Data Safety and Monitoring Board will not be instituted due to the low degree 
of risk with this study. The PI will oversee all data collection through the implementation of 
standardized data collection procedures. Safety monitoring will include careful assessment 
and appropriate reporting of AEs as indicated below, and will also include a regular 
assessment of the number and type of serious AEs.  Any serious AEs that might reasonably 
be due to the study will be reported to the CHOP IRB within 24 hours of its occurrence. Events 
that are not related to the study but classified as imminent risk to the subjects will be reported 
to the investigators and appropriate clinical referrals will be made.  
9.4.2 Risk Assessment 
The risks associated with this study are minimal and generally not in excess of those 
encountered in the hospital stay. Specifically, risks include: 1) breach of confidentiality; 2) 
discomfort from questions regarding cancer history and current symptoms; 3) inconvenience 
of study procedures. Because participants are assessed on a daily basis for whether they are 
medically able to participate in extended vitals checks, the medical risk for extending time 
between vitals checks by 2 hours is assumed minimal. If a participant develops a fever during 
the extended vitals checks portion of the study, there is a risk that it will not be detected for 
an additional 2 hours.  All participants can contact their nurse at any time between vitals 
checks for usual care or concerns such as fever.  All participants will be informed of these 
risks prior to participation and will be informed of the right to discontinue participation if they 
are uncomfortable with the study. If participants become upset, Dr. Barakat (licensed clinical 
psychologist, Director of Psychosocial Services in Oncology at CHOP) will assess the level 
of distress of the patient and determine the need for additional psychosocial support.   
9.4.3 Potential Benefits of Trial Participation 
The current research study seeks to improve sleep during the hospital stay for HSCT, although 
the short intervention period my not provide any direct benefit to the participants. The research 
proposed has the potential to improve clinical care of patients undergoing HSCT by reducing 
some overnight sleep disruptions, which may improve the patient’s functioning the following 
day.  

 
  
 
 
 
14 
9.4.4 Risk-Benefit Assessment 
Patients undergoing HSCT are a vulnerable and understudied group who exhibit many 
symptom management needs, including long-term sleep disruptions. Because poor sleep is 
implicated in psychosocial functioning and physical health, the results of the current study 
have the potential to identify a clinically relevant intervention that can improve sleep during 
hospital stays. Findings will inform HSCT patient care and future research on sleep in 
pediatric oncology. The potential benefits from the knowledge gained through this study, 
which has the potential to improve patient care and psychosocial outcomes, outweigh the 
minimal risks associated with participation.   
9.5 Recruitment Strategy 
After IRB approval, potential patient participants will be identified through the CHOP Stem 
Cell Transplant list and cleared by the patient’s primary oncologist. Potential participants will 
be invited to participate in the study during family education day prior to the stem cell 
transplant admission. Families will be given the “Fast Facts” flyer about the study.     
 
To enable the study coordinator scheduling and to allow for the extraction of EHR data, it will 
be necessary to maintain a “tracking” database that contains information about potentially 
eligible participants (e.g., parent name, child name, appointment time and location, date of 
birth, and MRN). Potential participant information will be added to the database from the 
Stem Cell Transplant List and will be updated through weekly chart review. This database 
will be maintained on a CHOP password-protected computer. All potential participants will 
be randomly assigned a participant ID number when their information is entered into the 
tracking database.  
9.6 Informed Consent/Assent and HIPAA Authorization 
Consent/assent for all participants will take place in person on the Stem Cell Transplant Unit 
at CHOP. Patients who are interested in participating will provide written consent 
(parents/legal guardians of children < 18 years old and AYA ≥ 18 years) and assent (children 
< 18 years of age).  A study team member will review the informed consent document with 
prospective participants and caregivers and answer any questions about study procedures. 
Separate consent forms will be reviewed and signed by patients and their caregivers, as 
needed. HIPAA Authorization will be obtained through a combined consent-authorization 
document. 
 
Nurse Consent Plan: After subjects have completed study participation, all nurses who were 
involved in the subject’s care during the extended vitals check period (either nights of days 
5-9 or 10-14) will be contacted to invite study participation.  Consent will take place on the 
Stem Cell Transplant Unit at CHOP or by phone prior to asking the nurse to complete the 
study acceptability measure. Written consent will be obtained from nurse subjects enrolled 
in person on the Stem Cell Transplant Unit at CHOP, while verbal consent will be obtained 
from nurse subjects enrolled via phone.  

 
  
 
 
 
15 
9.7 Payment to Subjects/Families 
9.7.1 Payments to subject for time, effort and inconvenience (i.e. compensation) 
Subjects will receive payments in the form of giftcards for taking part in this study. Subjects 
will receive $1 per day for wearing the actigraph, $1 for completing the daily sleep diary 
text messages, and $5 for completing each of the 4 self-report measure packets. Subjects 
will receive a $25 bonus for completing the study. Subjects can earn up to $75 for time and 
effort. Caregivers will receive $5 for completing each of the 4 caregiver report measure 
packets for a total of $20. If subjects withdraw, they will be paid on a pro rata basis for 
participation until study withdrawal.   
10 PUBLICATION 
The data on feasibility and acceptability of this pilot study will be submitted for publication 
by CHOP and Rutgers Univesrity investigators to a pediatric oncology journal at the 
culmination of the study. 
 
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APPENDIX 
A 
Consent with assent 
B 
Survey Items (Demographic form, psychosocial measures, Acceptability measure)