The Promoting Resilience in Stress Management (PRISM) Intervention: a Multi-site Randomized Controlled Trial for Adolescents and Young Adults Receiving Hematopoietic Cell Transplantation
Phase: NA
Conditions: Cancer, Bone Marrow Neoplasms, Anxiety, Depression, Quality of Life, Adherence, Medication, Coping Skills, Adolescent Behavior
Sponsor: Seattle Children's Hospital

Site Principal Researcher: Mallory Taylor, MD, MS
Protocol Version Number: 17 
Protocol Version Date: 11/28/2023
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PROTOCOL TITLE:
The Promoting Resilience in Stress Management (PRISM) Intervention: a multi-site randomized 
controlled trial for Adolescents and Young Adults receiving Hematopoietic Cell Transplantation
SPONSOR: Dana-Farber Cancer Institute
SITE PRINCIPAL INVESTIGATOR:
Mallory Taylor, MD, MS
Seattle Children’s Research Institute
1920 Terry Ave, CURE-4
Seattle, WA 98115
206-884-1582
Molly.taylor@seattlechildrens.org
Enrolling Sites: Seattle Children’s Research Institute (coordinating site), Children’s Hospital of Los 
Angeles, St. Jude Children’s Research Hospital (SJCRH) and University of Alabama, Birmingham 
(UAB). 
Dr. Taylor assumes responsibility for the conduct of the study at Seattle Children’s.  
Dana-Farber Cancer Institute (External Collaborators)

Abby Rosenberg, MD, MS, MA (Study Principal Investigator)
ClinicalTrials.gov Identifier: NCT03640325

Site Principal Researcher: Mallory Taylor, MD, MS
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Table of Contents
1.0
Objectives
  6
2.0
Background
  9
3.0
Inclusion and Exclusion Criteria
14
4.0
Study-Wide Number of Subjects
17
5.0
Study-Wide Recruitment Methods
17
6.0
Multi-Site Research
18
7.0
Study Timelines
19
8.0
Study Endpoints
19
9.0
Procedures Involved
19
10.0
Data and Specimen Banking
30
11.0
Data Analysis/Management
31
12.0
Confidentiality
35
13.0
Provisions to Monitor the Data to Ensure the Safety of 
Subjects
35
14.0
Withdrawal of Subjects
41
15.0
Risks to Subjects
41
16.0
Potential Benefits to Subjects
42
17.0
Vulnerable Populations
43
18.0
Community-Based Participatory Research
43
19.0
Sharing of Results with Subjects
43
20.0
Setting
43
21.0
Resources Available
44
22.0
Prior Approvals
44
23.0
Participant Incentive
44
24.0
Use of Social Media
45
25.0
Local Number of Subjects
45
26.0
Provisions to Protect the Privacy Interests of Subjects
45
27.0
Compensation for Research-Related Injury
45
28.0
Economic Burden to Subjects
45
29.0
Consent Process
45
30.0
Process to Document Consent in Writing
49
31.0
Drugs or Devices
49
32.0
Good Clinical Practice
49

Site Principal Researcher: Mallory Taylor, MD, MS
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ABBREVIATIONS AND DEFINITIONS OF TERMS
AYA
Adolescent and Young Adult
CRA
DNE
Clinical Research Associate
Days to Neutrophil Engraftment
CTRA
Conserved Transcriptional Response to Adversity
HCT
HRV
Hematopoietic Cell Transplantation
Heart Rate Variability
GVHD
Graft versus Host Disease
MEMS
Medication Electronic Monitoring System
PRISM
Promoting Resilience in Stress Management
RCT
Randomized Controlled Trial

Site Principal Researcher: Mallory Taylor, MD, MS
Protocol Version Number: 17 
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PROTOCOL REVISIONS (Original Approval Version 02/15/2018)
Protocol Revision 
(Version) Date
Revision
Rationale
Updated Study Team
Personnel Change
Addition of secondary 
aims to examine 
additional patient-
reported outcomes
Preliminary data from concurrent studies suggested clinically 
relevant patient-reported outcomes influenced by 
intervention; scientific interest
Addition of secondary 
aims to examine parent 
outcomes 
Preliminary data from concurrent studies suggested parents 
interested in participation; scientific interest
Adherence aim changed 
to exploratory
Final statistical calculations and discussion with pharmacists 
& consultants suggested insufficient power to detect 
associations.  
Procedures clarified
Consistency of institutional practices
Statistical plan clarified
Final (pre-launch) statistical plan confirmed with study team
8/10/2018
(PRIOR TO STUDY 
LAUNCH)
Centralized PRISM 
Manual 
Single document used between PRISM studies for 
consistency and generalizability of the PRISM intervention.
Changed RPCAs 
wording, formatting, and 
some questions 
Consistency of study procedures
Updated risks in 
protocol
Changing how study staff query suicidal/self harm thoughts 
as study staff are not trained to fully complete suicide 
assessments
Consent forms
implement app language to include iTunes and Google Play
10/17/18
Added recruitment flyer
Aid with recruitment
Add CD RISC 10
Study design update
Add phone consent
Maximize recruitment for infrequent clinic patients
1/2/19
Allow session #1 to be 
done remotely
Flexibility of study procedures
1/30/19
Add HRV as exploratory 
outcome of interest
Scientific Interest
Changes to payment 
schedule
Optimize enrollment and retention through individualized 
incentive structure
Adding raffle to win iPad 
Optimize subject retention with non-monetary incentive
6/20/2019
Allow for combining 
intervention sessions
Address feasibility challenges identified in prior studies 
associated with critically ill patients
Including St. Jude 
Children’s Research 
Hospital and University 
of Alabama, 
Birmingham, as 
additional study sites.
Augment recruitment to reach accrual goals. 
Including annual  on-site 
monitoring for 
participating sites
Quality assurance and data monitoring of non-primary sites. 
8/26/2019
Expanding window for 
Optimize subject retention and data completion 

Site Principal Researcher: Mallory Taylor, MD, MS
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baseline survey 
completion
10/3/2019
Add CTRA as 
exploratory outcome
Scientific Interest
Add autologous HCT to 
inclusion criteria
Augment recruitment to reach accrual goals.
1/13/2019
Removing costs of care 
& adherence 
questionnaires from 
AYA surveys
Minimize participant burden
Add opt-out approach 
letter 
Augment recruitment to reach accrual goals by minimizing 
need for in-person contact (e.g., during COVID-19 pandemic)
Add electronic 
consenting 
procedures/request 
waiver of consent 
documentation & 
alteration of HIPAA
Promote participant safety by minimizing need for in-person 
contact 
5/1/2020
Add COVID-19 impact 
instrument for AYAs and 
parents
Scientific Interest
Clarifying language for 
phone approaches
Clarification/specificity 
Clarifying language re: 
HRV monitor placement
Clarification/specificity
8/25/2020
Making Spanish 
instruments available in 
REDCap
Promote equity by offering electronic surveys for Spanish-
speaking participants 
11/3/2020
Allowing SCH PRISM 
interventionists to 
deliver sessions 
remotely to St Jude 
patients 
Fulfill interim staffing needs so enrolled patients can continue 
to receive intervention on schedule
Clarifying eligibility to 
include patients 
receiving HCT for any 
malignancy
3/05/2021
Expanding eligibility to 
include patients with 
bone marrow failure 
syndromes with 
predisposition (risk) for 
later malignancy
Clarify and augment enrollment goals to make up for limited 
accrual during the COVID-19 pandemic
10/24/2021
Expanding eligibility 
criteria for optional 
procedures to include 
Spanish-speaking 
individuals
Promote equity for Spanish-speaking participants

Site Principal Researcher: Mallory Taylor, MD, MS
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Text reminders to 
participants
Augment survey completion 
Enabling zoom chat 
during zoom-based 
PRISM sessions
Optimize ability to communicate with participants during 
virtual study activities
Accommodations in 
consent process for 
visually impaired 
individuals
Promote equity for visually-impaired participants
Additional incentive for 
survey completion
Augment survey completion
Clarification regarding 
survey administration 
procedures
Minimize participant burden, augment survey completion
Change medication 
adherence monitoring to 
optional procedure
Minimize participant burden
Update study team 
member information
Reflect change in CHLA site PI
2/18/2022
Add additional variables 
to be extracted from 
medical record for 
patients participating in 
HRV and/or CTRA 
optional components 
Scientific interest
11/28/2022
Update study team 
member information – 
change Principal 
Investigator 
Reflect PI personnel change at primary site 
12/16/2022
Editing to reflect that 
DFCI is the sponsor 
site. 
Reflect Abby Rosenberg’s move to DFCI.
2/3/2023
Added language to 
clarify sponsor (DFCI) 
and coordinating site 
(SCH) responsibilities. 
Fulfill sponsor’s regulatory requirements.
03/21/2023
Updating study team 
member information  
Removing team members from protocol

Site Principal Researcher: Mallory Taylor, MD, MS
Protocol Version Number: 17 
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1.0
Objectives
1.1 Overview
The experience of hematopoietic cell transplantation (HCT) among Adolescents and 
Young Adults (AYAs) with cancer is particularly difficult because age-related 
developmental challenges of identity, relationships, and vocation may add to the burden of 
cancer.  Compared to other age-groups, AYAs have poorer psychosocial outcomes 
including increased anxiety and depression and poorer adherence to oral 
immunosuppressive medications.  These outcomes may, in turn, predispose AYAs to 
disease-related morbidity and mortality such as graft-versus-host disease (GVHD) and/or 
cancer-relapse.  A potential barrier to improving these experiences may be that AYAs 
have few opportunities to develop the personal resources needed to handle adversity. We 
have previously developed the “Promoting Resilience in Stress Management” (PRISM) 
intervention for AYAs with serious illness.  This manualized, brief intervention is delivered 
in 4, 30-60 minute, one-on-one sessions, followed by a Parent/ Caregiver/ Spouse/ 
significant other inclusive meeting.  It targets skills in stress-management and 
mindfulness, goal-setting, positive reframing, and meaning-making.  All of these skills are 
associated with improved patient well-being in other populations, and preliminary findings 
from a recently closed pilot randomized controlled trial among AYAs with newly diagnosed 
cancer suggest PRISM is associated with improved health-related quality of life.  This 
study will build on our prior experience and fill a critical knowledge gap regarding PRISM’s 
impact among AYAs receiving HCT.  Thus, we will conduct a multi-site randomized 
controlled trial among N=70 AYAs (n=35 PRISM and n=35 usual care; ages 12-24 years), 
with the primary trial outcome of patient-reported symptoms of anxiety and depression.  
Secondary outcomes will include the cost-effectiveness of the intervention in this 
population and the impact of the intervention on parent well-being.  Exploratory outcomes 
will assess patient adherence to oral GVHD medications, as well as three biomedical 
variables associated with psychological distress; heart rate variability (HRV), days to 
neutrophil engraftment (DNE), and development of acute GVHD.  We hypothesize that 
AYAs who receive PRISM will report fewer mixed affective symptoms, demonstrate better 
adherence, and show improved biomedical outcomes, while their parents report improved 
quality of life and psychological distress.  We also anticipate the intervention will be cost-
effective.  In sum, this study offers an opportunity to expand the body of knowledge 
regarding methodologically rigorous and evidence-based psychosocial interventions and 
standards of care for AYAs with hematologic and other malignancies.  Ultimately, this 
research has the potential to reduce the burden of cancer in these vulnerable populations. 
1.2
Purpose of the Study Protocol
The protocol is intended to be used by all study staff as the approved procedures for 
conduct of the study.  
1.3
Primary Aim:  Evaluate the effect of PRISM compared to usual care on symptoms of 
anxiety and depression.  

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Primary Outcome Measure: AYA-reported mixed affective (anxiety and depression) 
symptoms 6-months post enrollment (measured with the Hospital Anxiety and Depression 
Scale).1 
Primary Hypothesis: PRISM will be associated with lower anxiety and depression 
compared to usual care.
1.4    Secondary Aims:
1.4.1
Evaluate PRISM’s impact on other key patient-reported outcomes 6-months 
following enrollment.
Outcome Measures: (a) Symptom Burden  (measured by the Memorial Symptom 
Assessment Score)2; (b) Health-Related Quality of Life (measured with the 
Pediatric Quality of Life [PedsQL] 4.0 Generic and 3.0 Cancer Modules)3,4; (c) 
Hopeful patterns of thought (Hope Scale)5; and, (d) resilience (Connor Davidson 
Resilience Scale, CDRISC-10).6,7  
Hypothesis: PRISM will be associated with (a) lower total symptom burden; (b) 
higher quality of life; (c) higher hope; and (d) higher resilience, compared to usual 
care.
1.4.2
Evaluate the cost-effectiveness of the PRISM intervention.  
Outcome Measure: Cost per Quality Adjusted Life Years (QALY)
Expected findings: PRISM will be cost-effective compared to usual care, 
considering a standard willingness to pay threshold of $150,000 per QALY 
gained
Exploratory Outcomes: (i) PRISM’s cost utility as a function of treatments related 
to patient-reported anxiety and depression; and, (ii) PRISM’s cost per clinically 
relevant consequence such as change in mental health score or adherence.  
1.4.3
Evaluate the impact of PRISM on parent outcomes 6-months following 
enrollment.
Outcome Measures: Health-Related Quality of Life (SF-36)8;  anxiety 
(Generalized Anxiety Disorder Screener, GAD-7),9 and depression  (PHQ-8),10,11   
Hypothesis: Parents of AYAs who receive PRISM will report higher quality of life 
and lower psychological distress compared to parents of AYAs in usual care.
Exploratory Outcome: Family Experience (selected items from Hospital 
Consumer Assessment of Healthcare Providers and Systems [HCAHPS] 
survey).12
1.4.4 Describe individual and group 6-month trajectories for patient reported 
outcomes of usual care and PRISM participants. 
1.5
Exploratory Aims
1.5.1
Evaluate the effectiveness of PRISM compared to usual care in promoting 
adherence to oral GVHD prophylaxis.

Site Principal Researcher: Mallory Taylor, MD, MS
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Outcome Measures: (i) Medication Electronic Monitoring Systems (MEMS) cap 
electronic adherence assessments during the remaining 6 months following initial 
hospitalization for HCT. 
1.5.2
Prospectively describe associations between PRISM, patient reported 
anxiety and depression, and stress biomarkers.
Outcome Measures: (i) Days from HCT to neutrophil engraftment, (ii) prevalence 
and severity of GVHD (revised Seattle Criteria), (iii) heart rate variability (as 
measured by the interbeat interval (IBI), (iv) gene expression profile.    
1.6
Rationale for the Selection of Outcome Measures
The primary outcome (patient-reported anxiety and depression symptoms) was selected 
not only because it is a prevalent and clinically important element of AYA wellbeing 
during and after HCT, but also because our pilot experience suggests PRISM may 
prevent the development of distress over time.  Additional AYA patient-reported 
outcomes were selected because they are clinically relevant norms in psychosocial 
intervention research.  Our prior experience suggests PRISM is associated with 
improved quality of life, hope, and resilience, for example, and the present study will 
confirm if these findings are generalizable in this new population of youth receiving HCT.  
We chose to measure cost-effectiveness with cost per QALY because this ratio has 
established thresholds with which to define value.  We will capture additional measures 
of cost-effectiveness (e.g., cost as a function of anxiety/depression and cost-
effectiveness for various levels of adherence)) in order to inform future clinical guidelines 
and research.  Prior evidence suggests that parent and child outcomes are strongly 
correlated; it is thus important to determine if a child-centered intervention can also 
improve parent outcomes and experiences.  Emerging data indicate anxiety and 
depression can impact cancer-related outcomes through immune-mediated 
mechanisms.  Neutrophil engraftment and GVHD are both immunologic phenomena that 
have been associated with psychological disposition in the HCT literature, and are 
documented as part of clinical standard of care.  HRV is a commonly used, noninvasive 
stress biomarker with published normative values. The “Conserved Transcriptional 
Response to Adversity (CTRA)” RNA transcription pattern is observed following 
exposure to stress, and results in increased inflammation, which is an important 
mediator of acute and chronic co-morbidities.  Lastly, adherence was selected as a 
clinically important exploratory outcome because of its potential impact on late effects 
including GVHD.  
2.0
Background
2.1
Prior Literature and Previous Studies
2.1.1
Outcomes and Barriers to Improvement among Adolescents and Young 
Adults with Cancer
Adolescents and Young Adults (AYAs) with cancer have high risks of poor 
physical and psychosocial outcomes, perhaps because cancer disrupts normal 
developmental experiences like establishment of independence, identification of 

Site Principal Researcher: Mallory Taylor, MD, MS
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personal, social, and sexual identities, completion of education, and pursuit of 
vocational goals.13-17 AYA survivors have ongoing challenges including physical 
impairment, psychological distress, infertility, and discrimination in employment 
and insurance.18-20  These challenges impair survivors’ abilities to contribute to 
society. Compared to adults without a history of cancer, AYA survivors have 
projected annual excess medical expenditures of $3170 and annual productivity 
losses of $2250 per person.21  Extrapolating these costs across the lifetime of 
AYAs implies excessive societal economic burdens.  Targeting AYA well-being 
may therefore improve AYA and societal outcomes.22  
A potential explanation is that AYAs lack skills to navigate the adversities of 
cancer.  Positive psychological resources may mitigate negative and facilitate 
positive outcomes.23,24 “Resilience” is evidenced by sustained emotional and 
physical well-being after significant stress.25  The study of resilience in cancer 
has lacked consensus of either definitions or outcomes indicative of 
resilience.25,26  However, several personal resources are consistently associated 
with resilience among AYAs and older adults with cancer,24,27,28 and among 
parents of children with cancer.29,30  These include stress-management, problem-
solving and goal-setting skills, benefit-finding, and the ability to make meaning 
from adversity.  We term this group of variables “resilience resources.”  
Bio-behavioral models suggest that resilience resources relate to long-
term quality of life, health behaviors, immune function, and overall health 
and well-being.31 Pre-transplant depression has been associated with 
lower overall survival and higher risk of acute GVHD among HCT 
recipients.  Additionally, studies of autologous HCT recipients suggest 
greater optimism and lower anxiety was associated with accelerated 
neutrophil engraftment following transplant.  Genome science studies are 
beginning to map out the underlying molecular pathways responsible for 
these interrelated mental and physical health outcomes in cancer. Acute 
or chronic stress can induce a conserved transcriptional response to 
adversity (CTRA) gene expression profile - a systematic shift in gene 
expression that results in increased expression of genes involved in 
inflammation.32-34 Conversely, positive psychological states can activate 
protective gene expression patterns that promote healthy immune system 
function, which is particularly salient in the HCT setting. Hence, skills-
based interventions bolstering these resilience resources may improve 
both psychosocial and biological disease outcomes.31 
These resources are particularly important in the setting of Hematopoietic Cell 
Transplantation (HCT). AYAs receiving HCT experience high burdens of medical 
morbidity and mortality, and comparatively poor health-related quality of life.35-42  
Anxiety is highly prevalent before the transplant, and 40% of patients experience 
depressive symptoms in the 6 months that follow.  This “stress reaction” is 
associated with behavioral problems and peer isolation, and persists for a third of 
patients.43  Assisting AYAs to navigate the early transplant period may minimize 
escalation to significant distress.  Further, professional behavioral health 

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specialists may be scarce for the subset with serious distress.44,45  Experts 
therefore suggest “universal” preventative psychosocial oncology care designed 
to “help patients help themselves.”44-46
The first 6 months after HCT are important.  Stress and distress before and in the 
first 6 months after HCT contribute to poor pharmaco-adherence, in turn 
increasing risks of cancer recurrence and Graft Versus Host Disease 
(GVHD).41,47-49 Adherence rates among HCT-AYAs range from 40% to 90%; only 
56% demonstrate “perfect adherence” and most take only 73% of their 
prescribed doses.50  Although non-adherence is a well-described problem,48,51,52 
few interventions have improved it.53  Early, psychosocial interventions targeting 
psychosocial wellbeing and self-efficacy may be more effective.43,49,53,54 
Access to early psychosocial interventions is limited.  Despite national 
recommendations for early integration of psychosocial care in pediatric and AYA 
oncology,55-60 barriers remain.  These include diverse models of assessment, 
service delivery, and staffing.55  Pediatric cancer centers differ in size and 
location; they have variable, often limited, resources and funding for psychosocial 
services.57,61,62  Some may not treat a sufficient number of patients to justify the 
costs of a comprehensive multidisciplinary team.61,62  While centers may provide 
training for staff to effectively support patients and families (e.g., workshops on 
empathic listening, communication, problem-solving, and health literacy),63-65 
standardized, evidence-based, developmentally-appropriate interventions for 
AYAs with cancer are not well described.16,55,56,66-68  
Practical challenges limit the success of traditional behavioral interventions.  
Time-commitments associated with traditional psychological interventions like 
cognitive behavioral therapy (CBT) may be prohibitive for AYAs.  The average 
refusal rate for CBT in adolescent chronic disease settings is 37%; subsequent 
attrition is up to 32%.69  Shorter skills-based interventions may be more 
successful.70  Additionally, stigma and costs associated with traditional mental 
health services may hinder their uptake.55-57,61,62,71,72  AYAs learn and 
communicate differently than younger and older patients, necessitating age-
appropriate methods.73  Furthermore, CBT is designed for patients with 
maladaptive coping, whereas AYAs may be helped to avoid maladaptive 
behaviors through brief preventive learning.
Psychosocial interventions must also be cost-effective.  With increasing costs of 
healthcare, high quality and cost-effective interventions are critically important.  
Recent studies suggest psychosocial oncology interventions have favorable cost-
effectiveness.74-77 Economic analyses focusing on cost-utility, expressed in cost 
per Quality Adjusted Life Year (QALY) gained, have been recommended 
because they include standardized methods and established thresholds for 
willingness to pay (typically $150,000 per QALY gained).77-80  However, cost per 
QALYs may not capture all outcomes important to patient-stakeholders.81 
Corresponding cost-consequence analyses may better align with informational 
demands of decision-makers because they list and compare all relevant direct 

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and indirect costs and consequences (e.g. cost per change in anxiety and 
depression scores).  For this reason, the Second US Panel on Cost-
Effectiveness in Health and Medicine recommends both approaches.78
Stress and 
coping theory 
(Figure 1)82 
provides an 
excellent 
platform for 
intervention 
development.  
This theory 
suggests three 
categories of 
resources to 
maintain 
psychological 
well-being 
during and after 
serious illness: 
(1) dispositional 
factors (e.g., optimism); (2) situational factors (e.g., stress-management and 
goal-setting skills); and, (3) coping processes to create positive meaning (e.g., 
cognitive reframing). Among older adults with cancer, stress-management shows 
promise at the beginning,83 middle,84 and end of treatment,85 and meaning-
making may improve quality of life.86  Among well AYAs, individual differences in 
goal-seeking and problem-solving are associated with psychosocial well-being.87 
Among AYAs with chronic disease, positive re-appraisal of stressors reduces 
distress, improves adherence,87 and optimizes quality of life.88,89 
2.1.2
The Promoting Resilience in Stress Management (PRISM) intervention
Our central hypothesis is that promoting resilience resources will improve 
outcomes for AYAs and their families.  We followed a stepwise approach to 
testing this hypothesis.  
Concept and survey development. First, we conducted a cross-sectional, mixed-
methods study to explore the construct of resilience in pediatric and AYA 
oncology.  Qualitative findings directed the development a conceptual 
framework30 and a survey comprised of validated instruments to measure 
corresponding patient-centered outcomes [the “Resilience in Pediatric Cancer 
Assessment” (RPCA)].29,30,90 Quantitative findings confirmed associations 
between lower resilience resources and higher distress, lower social function, 
and poorer health behaviors.29 

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Prospective study of AYA perceptions of resilience.  Second, in the “Resilience 
in Adolescents and Young Adults with Cancer” study, we collected survey data 
and conducted consecutive 1:1 semi-structured interviews with AYA patients at 
the time of their diagnosis, 3-6 and 12-18 months later.28,91,92 Several 
participants received HCT during the study.  Thematic analyses suggested that 
AYAs endorse the need for strong resilience resources, but that they lack the 
skills.  Specifically, AYAs stated stress-management, goal-setting skills, “staying 
positive,” and “making meaning” from adversity were essential to their well-
being.28  
Intervention Development.  These studies provided rationale for the design of a 
novel intervention to promote resilience resources, the “Promoting Resilience in 
Stress Management” (PRISM, Table 1).93 PRISM is based on stress and coping 
theory (Figure 1),82 our prior research, and successful interventions described in 
other populations.  It is manualized (i.e., it has been standardized via 
comprehensive protocols).  The initial design was refined with expert opinion 
and interviews with patients, psychologists, and social workers.  Details are 
described below. Briefly, PRISM’s overall objective is to increase resilience 
resources at times of high stress, thereby alleviating distress and improving 
quality of life.  
Feasibility and Acceptability study of PRISM Intervention.  We completed a 
formative study of PRISM among 24 AYAs to determine the optimal content and 
timing of PRISM sessions.  We found it to be feasible and highly valuable to AYA 
patients and parents.93 Eighty percent of AYA participants completed the 
intervention and feedback was universally positive: “This was so helpful, I wish 
we had done this sooner,” or “I think it’s good techniques to use, definitely.  I am 
teaching my little sister.  I’m sure it can help her, too.”
PRISM Pilot RCT (clinicaltrials.gov NCT 02340884).  Next, in a phase II RCT 
testing PRISM efficacy among AYAs with new or recurrent cancer, we refined 
processes of enrollment, randomization, implementation, and data collection.  We 
completed our target enrollment ahead of schedule; enrollment rates were 78%.  
Table 1. PRISM intervention content 
Topic
Details
Format
1.
Managing Stress
Mindfulness techniques, relaxation strategies, obtaining social support
2.
Goal-setting
Setting specific, realistic, desirable goals, planning for roadblocks
3.
Positive Reframing
Recognizing negative self-talk, replacing with positive, realistic, 
manageable ones
4.
Meaning Making
Identifying benefits, purpose, meaning, or legacy from cancer experience 
One-on-One
5.
Coming Together
Discussion with parents/caregiver/spouse/significant other  about what was 
learned, what helped, what they can do to help 
Parent/Caregiver/ 
Spouse/Significant other 
inclusive meeting 
6.
Boosters
Personal contacts and/or digital modules to practice, further develop, and 
track skills.  
One-on-One or Digital
Note: Sessions delivered approximately every 1-2 weeks, arranged in advance in conjunction with clinic and hospital visits or can 
be done via phone or other web based communication (i.e., zoom, WebEx, skype, blue jeans, go to meetings, WhatsApp, etc.)  
(with the exception of session 1).

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Attrition (20%) was similar on the PRISM and usual care arms, and primarily due 
to medical complications.  
The primary objective of the phase II RCT was to assess patient-reported 
resilience. Final analyses suggest PRISM improved patient reported resilience 
and 
quality 
of 
life, 
and 
reduced 
psychological 
distress 
(Table 
2).
Table 2. Mixed linear model estimates of change in instrument scores associated with PRISM 
compared to usual care in phase II RCT
Outcome (instrument)
Beta (95% CI)
p-value
Resilience (CDRISC-10)
3.0 (0.5, 5.4)
0.02
Generic Quality of Life (PedsQL SF-15)
7.2 (-0.8, 15.2)
0.08
Cancer-specific Quality of Life (PedsQL Cancer)
9.6 (2.6, 16.7)
0.01
Global Psychological Distress (Kessler-6)
-2.1 (-4.1, -0.2)
0.03
2.2 
Rationale for this Study
While these findings suggest PRISM is effective, key questions remain: (1) Does 
supportive care with PRISM prevent clinically important symptoms of anxiety and 
depression among AYAs receiving HCT?; (2) Is PRISM cost-effective compared to 
supportive care without PRISM?; (3) Does it promote medication adherence? and,  (4) Is 
PRISM associated with measurable biomarkers of stress and resilience? These 
questions are important because high-value interventions must not only provide clinical 
benefit, but also be cost-effective.94 The current study will build on our prior success and 
expertise to answer these questions. (Figure 2).  

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3.0
Inclusion and Exclusion Criteria
3.1
Recruitment and Screening: 
We will recruit consecutive AYAs and their primary caregivers from outpatient Clinics 
and inpatient wards of Seattle Cancer Care Alliance (Seattle Children’s Hospital and 
Fred Hutchinson Cancer Research Center),Children’s Hospital Los Angeles (CHLA),  St. 
Jude Children’s Research Hospital (SJCRH), and University of Alabama at Birmingham 
(UAB).  Research Associates (RAs) at each site will screen patients via review of the 
new transplant arrivals list, clinic rosters and sign-outs, communication with clinicians, 
and attendance at HCT conferences, followed by a medical chart review to very 
eligibility. 
For Seattle Children’s Hospital participants, recruitment will be conducted as follows: 
The study will be initially introduced to eligible families through either a study information 
flyer or opt-out letter. When possible, BMT clinic staff will distribute flyers to patients on 
intake day with the message that “someone will be contacting you to talk about this 
more” message. RAs will then conduct in-person recruitment in clinic waiting rooms, at 
clinic visits and/or inpatient hospital rooms. RAs will then discuss the project with 
patients and their parents and answer questions. Consent conference may be conducted 
directly following the approach or at a later date, depending on family preference. 
Phone-based recruitment methods will be used in cases where in-person recruitment is 
not possible/feasible. This includes instances when in-person interaction would pose 
infection risk to patients (e.g., during COVID-19 pandemic), instances where patients 
are coming to clinic infrequently, or when in-person recruitment may cause unnecessary 
subject burden and obtaining consent by phone/video would achieve the same purpose 
without reducing subject informedness. This includes instances such as providers 
interrupting the consent conference, when the day is “not good” for the family to be 
approached, or when illness status in which the patient is not cognitively able to provide 
consent/assent that day. In these instances, eligible patients (or parents, when patient is 
under 18) will be mailed a letter or sent an e-mail introducing them to the study and 
giving them the opportunity to “opt out” of future contact if desired. If potentially eligible 
patients who receive the mailing do not opt-out of being approached about the study, an 
RA will then call them to assess interest. RAs will call a maximum of six times until 
contact is made, with a maximum of 3 voicemails. Once direct contact is made (i.e., 
having a conversation), follow up calls or texts will only occur if the family expresses 
interest in the study or requests a callback. Once they contact the family, the RA will use 
a phone approach script to explain the study. If the family is interested, the RA will e-mail 
or mail a copy of the consent form to the family and schedule a later time for a 
phone/video consent conference. Should families approached via phone prefer to 
continue to discuss the study or consent in person, we will arrange a follow-up 
conversation regarding the study at the time of their clinic or inpatient hospital visit or 

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while they plan to be at the hospital. Text communication will occur only after initial 
contact is made with a family via a non-text method.
Consent conferences will be conducted in a private consult room, clinic room or in the 
patient room (in-hospital) or via phone or videoconference. Videoconference will only be 
used if specifically requested by the participant, via WebEx or Zoom. Videoconference or 
phone-based consent conferences will NOT be recorded. Patients and families will be 
given an addendum to the consent form to participate in the optional heart rate 
variability,CTRA gene expression (blood draw), or medication adherence monitoring 
components of the study.  We will emphasize there will be no penalties if patients or 
families opt out of the optional portions of the study. These optional procedures will be 
presented at the time of the consent conference. All patients fulfilling eligibility criteria will 
be eligible for the HRV and CTRA components of the study. Only patients receiving 
allogeneic HCT will be eligible for the medication adherence monitoring component. . 
Parents do not take part in the optional components. In cases where it is necessary to 
minimize in-person contact with participants to minimize exposure risk (e.g., during 
COVID-19 pandemic), the HRV component will not offered and families will be verbally 
informed of this justification.  
We recognize potential risks for adolescents involved in recruitment; there could be 
embarrassment or discomfort for adolescents if asked to participate. Adolescents may 
feel coercion to be part of the study. To mitigate these risks, we will emphasize the 
voluntary nature of the study to adolescents and parents and that the study will in no 
way impact or influence clinical care.  We will let adolescents know that their information 
will be kept confidential and that qualitative interview transcripts will be de-identified and 
audio recordings destroyed after transcribing. We will let adolescents know that they can 
change their mind about participating and may decide to withdraw from the study at any 
time. 
Each of the participating sites has significant experience with clinic recruitment for 
studies and has developed processes to ensure best practices for participant 
recruitment. These procedures and scripts also emphasize that any potential coercion 
on the part of parents should not take place, and that adolescents’ decision for or 
against participation in the study does not affect the clinical care they receive.
The investigators and staff will be available to answer any questions from potential 
participants via phone or email throughout the study. We will emphasize that the 
decision of whether or not to be part of this study does not affect participants’ 
involvement in the PRISM study, or their ongoing care at their respective institutions.
3.2
Eligibility Criteria:
3.2.1
Inclusion Criteria FOR AYA PATIENTS:
3.2.1.1
Age 12-24 years

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3.2.1.1.a
Patient aged 12-17 years: has signed informed assent and their 
parent/legal guardian has signed informed consent for study 
participation.
3.2.1.1.b
Patient aged 18-24 years: has signed informed consent for study 
participation.
3.2.1.2
Receiving allogeneic or autologous HCT for treatment of malignancy or 
bone marrow failure syndrome at Seattle Cancer Care Alliance (Seattle 
Children’s Hospital and Fred Hutchinson Cancer Research 
Center),Children’s Hospital Los Angeles (CHLA), University of Alabama 
at Birmingham (UAB)  or St. Jude Children’s Research Hospital (SJCRH). 
3.2.1.3
Within 4 weeks of their HCT date (“day zero”) (if prior, their planned HCT 
date)
3.2.1.4
Patient able to speak in the English language
3.2.1.5
Patient able to read in the English or Spanish language
3.2.1.6
Cognitively able to participate in interactive interviews
***Inclusion criteria for medication adherence component only: 
Patient receiving allogeneic HCT (i.e., receiving standard prophylaxis 
against Graft-Versus-Host Disease [GVHD]).  
*Note: Concurrent parent participation is not required for AYA patient 
participation
3.2.2
Exclusion Criteria FOR AYA PATIENTS:
3.2.2.1
Patient refusal to participate (any age), or parental refusal to participate 
for patients less than 18 years of age
3.2.2.2
Cognitively or physically unable to participate in interactive interview
3.2.2.3
Patient unable to speak in the English language
3.2.2.4
Patient unable to read in the English or Spanish language
3.2.2.5
Patient not receiving allogeneic or autologous HCT for treatment of 
malignancy or bone marrow failure syndrome.
***Exclusion criteria for medication adherence component: Patient 
receiving autologous HCT (i.e., not receiving standard prophylaxis against 
Graft-Versus-Host Disease [GVHD]).  
3.2.3
Inclusion Criteria FOR PARENTS or GUARDIANS OF AYA PATIENT 
PARTICIPANTS to participate in SURVEY-COMPLETION
3.2.3.1
AYA Child of parent or guardian agrees to participate in study

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3.2.3.2
AYA child participant provides verbal assent or verbal consent if 18 or 
over for parent or guardian to complete surveys.
3.2.3.3
One parent per patient parent dyad 
3.2.3.4
Parent/Guardian is cognitively and physically able to participate
3.2.3.5
Parent/Guardian is able to speak and read English or Spanish language
3.2.3.6
Parent/Guardian participant has signed informed consent for study 
participation
3.2.4
Inclusion Criteria FOR PARENTS, CAREGIVER, SPOUSES, OR 
SIGNIFICANT OTHERS of AYA PATIENT PARTICIPANTS to participate in 
PRISM SESSION 5, “Coming Together” 
3.2.4.1
AYA agrees to participate in study
3.2.4.2
AYA randomized to PRISM intervention arm of study
3.2.4.3
AYA provides verbal assent or verbal consent if 18 or over for parent, 
caregiver, spouse, and/or significant other to be present during this 
session.
3.2.4.4
Parent/Caregiver/Spouse/Significant other is cognitively and physically 
able to participate 
3.2.4.5
Parent/Caregiver/Spouse/Significant other is able to speak and read in 
English or Spanish
3.2.4.6
Parent/Caregiver/Spouse/Significant other participant has signed 
informed consent for study participation
3.2.5
Exclusion Criteria for PARENTS, GUARDIANS, CAREGIVER, SPOUSES, 
OR SIGNIFICANT OTHERS of AYA PATIENT PARTICIPANTS in SURVEY 
COMPLETION or PRISM SESSION 5, “Coming Together”
3.2.5.1
AYA refusal to participate
3.2.5.2
Parent/Guardian/Caregiver/Spouse/Significant other participant is <18 
years of age
3.2.6 Special Populations:   Please see section 17 for details about special populations 
including adults unable to consent, minors (individuals who are not yet adults), wards 
of the state, pregnant women, and prisoners. 
4.0
Study-Wide Number of Subjects

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Number of subjects: We will enroll and randomize a total of n=90 AYAs from the four sites in 
order to reach our target n=70 of evaluable patients with complete data at the primary endpoint 
(Table 3).  Note that both AYA patients and their parents/legal guardians will be enrolled when 
possible in order to collect accurate costing data.  The rationale is that much of the day-to-day 
costs such as transportation and missed work will be experienced by PARENTS rather than 
AYAs.  
 
5.0
Study-Wide Recruitment Methods
All recruitment methods will be conducted and overseen by local sites per local practices.  
There are no study-wide recruitment methods (e.g., no call centers or national 
advertisements); however, the trial will be listed at clinicaltrials.gov and therefore identified 
by national search engines.  
6.0
Multi-Site Research
6.1 
Enrolling sites. We will recruit consecutive AYAs and their primary caregivers from 
outpatient clinics and inpatient wards at the Seattle Cancer Care Alliance (Seattle 
Children’s Hospital and Fred Hutchinson Cancer Research Center), Children’s Hospital 
Los Angeles (CHLA), St. Jude Children’s Research Hospital (SJCRH) and University of 
Alabama at Birmingham (UAB). The lead study team member from SCH will travel to 
each participating site for site initiation where study teams will participate in minimum a 
day long training.
6.2 
Coordinating site responsibilities. The Seattle lead CRA will ensure the following: 
6.2.1
All sites have the most current version of the protocol, consent document, and 
HIPAA authorization.
6.2.2
All required approvals have been obtained at each site (including approval by the 
site’s IRB of record or any other contingencies and rules required by the NIH).
6.2.3
All modifications have been communicated to sites, and approved (including 
approval by the site’s IRB of record) before the modification is implemented.
6.2.4
All engaged participating sites will safeguard data as required by local 
information security policies.
Table 3. Annual number of AYAs (12-24 yrs-old) who are 
eligible, enrolled, and evaluable at 6 months
Site
Total
Eligible
Enrolled
Evaluable
SCCA
18
16
11
10
CHLA
12
11
7
6
St. Jude
10
9
6
4
UAB
10
8
6
4
Total/Year
50
44
30
24
Total for 36-month recruitment period:
90
>70

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6.2.5
All local site investigators conduct the study appropriately.
6.2.6
All non-compliance with the study protocol or applicable requirements will be 
reported in accordance with local policy.
6.3 Study oversight. 
Overall study oversite remains the responsibility of Dr. Abby Rosenberg at the Dana-Farber 
Cancer Institute. Due to her new engagement at Dana-Farber, she will have frequent 
check-ins with the coorninating center, Seattle Children’s, to monitor progress on 
enrollment, intervention delivery, data completion, and protocol adherence. She will also be 
involved in monthly multisite calls to maintain up to date on study progress.
Seattle Children’s will remain the coordinating center and maintain the following 
responsibilities on Dr. Rosenberg’s behalf. The SCH lead CRA will have at minimum 
monthly meetings with each site to review and troubleshoot trial conduct and questions, 
including (but not limited to) regulatory oversight, recruitment, data collection, intervention 
delivery, clinical concerns and/or other concerns.  The lead CRA will review current 
documents and any changes that are upcoming or approved.  The lead CRA will review 
any interim results or necessary information the sites should have as well as all study 
procedures, including modifications, updates, study closure, etc. The DFCI (Junkins) lead 
interventionist will have at minimum twice monthly meetings with interventionists to 
administer re-training as needed and review intervention delivery and fidelity. A lead SCH 
study team member will conduct yearly on-site or remote monitoring of participating sites 
for review of study documents and databases. This will include verification of 
consent/assent forms, documentation of eligibility, completeness of Case Report Forms 
(CRFs), and regulatory submissions and approvals. 
7.0
Study Timelines
Study activities include start-up, conduction and oversight, followed by dissemination of results.  
Projected activities and deliverables are described in Table 4.
Table 4. Timeline of research activities 
Year 1
Year 2
Year 3
Year 4
Year 5
Activities
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
Study Implementation Activities
IRB Protocol Submission)
Design of Case Report Forms and RedCap database
Conduct of PRISM RCT for AYAs with cancer
Recruitment
Follow-up
Monitoring and Analyses

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8.0
Study Endpoints
8.1
Primary Endpoint:  6-month follow-up of last AYA participant including patient-reported 
outcome survey completion.
8.2
Secondary Endpoints:
8.2.1 6-month follow-up of last parent participant including parent-reported outcome 
survey completion.
8.2.2
6-month costing data collection including parent- and parent-reporting costing 
forms, and medical record extraction
6-month follow-up of last AYA participant by Medication Electronic Monitoring 
System (MEMS) cap electronic adherence assessment.
9.0
Procedures Involved
9.1
 Enrollment. Once consent documents are signed and all questions addressed, the 
consenting RA or study staff will register the patient in the RedCap System.  
Randomization will not occur until after the baseline Resilience in Pediatric Cancer 
Assessment (RPCA) surveys are collected (see below).  Site RAs will maintain original 
copies of all consent forms and fax/email copies to the coordinating center for secure 
storage and tracking purposes.  
9.2 
Randomization. 
As a quality control measure, a randomization log will be maintained at SCH to track the 
participant ID, stratum, randomized assignment, and date of randomization.  Patients will 
be randomized only after completion of the baseline surveys and in a 1:1 ratio to receive 
usual, non-directive, supportive care without PRISM (“control” arm) or with PRISM 
(“experimental” arm). Randomization will be stratified by age (patients ages 12-17 
versus ages 18-24 and site.  Biostatisticians who will conduct data analysis will be 
blinded from the treatment group allocations. Throughout the screening period until 
allocation of the control or PRISM, participants will be assigned a screening number, 
according to the chronological order of screening. Once enrolled, the participant will be 
assigned a study ID. 
9.3 
Scheduling of study procedures with participants.  
9.3.1 Baseline Survey Completion Upon enrollment, study staff will deliver the 
baseline survey in participant’s preferred language (English or Spanish). For both 
English and Spanish, the study will first be offered by email via REDCap or via 
Monitoring of PRISM intervention fidelity
Interim data analysis (design, program, and run)
Full data analysis (design, program, and run)
Manuscript submission and dissemination

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REDCap on a study team iPad. Upon request, staff will offer paper-pencil 
versions and/or interview-based versions (interviews only available in English).
9.3.2 Randomization. Patients will be randomized following completion of baseline 
RPCA surveys.  Staff will aim for the RPCA surveys to be completed immediately 
following enrollment.  Baseline surveys will be collected within the first two 
weeks.  If surveys are not completed within this time-frame, staff will return to the 
participant to confirm interest and offer a digital (or, when requested paper-pencil 
or interview-based) survey to be completed in real-time.  If participants do not 
complete the survey at that time, they will be removed from the study.  For those 
who do complete the survey, following completion, staff at each site will receive 
their randomization allocation.  They will then return to patients and families to 
relay this information and create a study calendar outlining survey due-dates 
and, where relevant, PRISM sessions. Where relevant, PRISM-sessions will be 
scheduled approximately every other week, beginning within the first week of 
enrollment.
9.4 
Overview and Session Details of Intervention Arm.  
The original Promoting Resilience in Stress Management (PRISM) intervention consists 
of four, 30-50 minute, one-on-one, in-person sessions approximately 1-2 weeks apart 
plus a 5th session for AYA and selected parent/caregiver/ spouse/significant other 
together (Table 1).  Supplemental materials (e.g., media-links to resources, worksheets, 
text-based reminders, and a digital app to track and practice skills) are provided between 
sessions. The digital app is an interactive platform to practice the same PRISM 
exercises that are taught during the in-person sessions with the same intervention script 
(please see training manual and fidelity document for script).  To increase translation 
and wider application of PRISM in the future, a trained non-clinical research associate 
administers it, as described in previous models and our pilot studies.93,95  The 1st session 
occurs within 2 weeks of enrollment.  Other sessions are scheduled around patient clinic 
and/or hospital visits (depending on concurrent illness and medical needs).  Following 
the 5th session, intervention participants will be offered every other week “booster” 
contacts until they reach the 6 month point from enrollment.  Although in person visits 
are preferred, if a patient explicitly requests or if scheduling barriers preclude in-person 
visits, all sessions and boosters may be done via phone or other web based 
communication (i.e., zoom, WebEx, skype, blue jeans, go to meetings, WhatsApp, etc.) .
Details of the sessions are listed in Table 1.  Briefly, session 1 (“Stress-management”) 
focuses on mindfulness skills including deep breathing and relaxation techniques, and 
building awareness and acceptance of stressors.  Session 2 (“Goal setting”) teaches 
simple goal-setting skills (e.g., identifying realistic, concrete and actionable goals, 
planning steps towards their achievement, preparing for roadblocks and identifying 
alternative pathways).  Session 3 (“Cognitive Restructuring”) trains patients to recognize 
negative emotions and demoralizing self-talk and helps them develop skills to reframe 
these in a positive light.  Session 4 (“Benefit Finding”) focuses on finding meaning and/or 
benefitting from difficult situations (including their cancer).  

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The final 5th session (“Coming together”) allows patients to reflect on the skills they have 
learned, to identify those that resonate and work for them, and to share their thoughts 
with parents. During this last session, selected parent(s)/caregiver(s)/ spouse/significant 
others are explicitly asked to join and listen to the discussion.  Study personnel will 
review and share with parents/caregivers/ spouse/significant others the explicit skills 
endorsed by patients and encourage shared conversation about how  
parents/caregiver/spouses/significant others and the patients can support one another.  
For families where parents prefer Spanish or another non-English language, this final 
session will be conducted with a certified interpreter of the native language of the parent. 
In the phase II RCT, the majority of the PRISM arm opted into the fifth session even 
though it was an optional study procedure in that study (n = 38 out of 40 who completed 
all four PRISM sessions). However, patients may still opt out of the coming together 
session if they request to do so explicitly.  We will continue to follow them and offer an 
optional booster session with the interventionist in lieu of the parent/caregiver/ 
spouse/significant other inclusive meeting in these cases. Additionally, the coming 
together session may not be feasible if the parent/caregiver/spouse/significant other has 
not agreed to be a part of the study. In such cases, we will re-offer participation in real 
time.  If parents/caregivers/ spouse/significant other still decline, then we will skip the 
parent/caregiver/spouse/significant other inclusive meeting.  
Sessions may be combined (maximum 2 sessions per meeting) based on patient 
preference/research discretion for reasons including (but not limited to): illness 
severity/progression or patient availability. 
All of the sessions of the PRISM will be audio-recorded as possible, barring issues with 
the recorder or refusal of the patient to be recorded. Administrators of the PRISM will 
explain that the sessions will be taped and reviewed by the study team with the goal of 
assessing adherence to the protocol, inclusion of required elements, and 
presence/absence of additional information with the exception of the feedback 
questions. As possible, the PI or supervising team member at Seattle Children’s will 
review the first of each 5 sessions for each interventionist, and score them for fidelity 
using a standardized tool (see appendix.). After the first 5 sessions are reviewed for 
each interventionist, one of each 5 subsequent sessions will be randomly selected to be 
monitored for fidelity, with feedback and re-training regarding adherence to protocol and 
approach will be refined if needed.    
Participants on the intervention arm will be offered every other week “booster” contacts 
until they reach the 6 month point from enrollment. These will include brief (10-20 
minute) in-person contacts in clinic, in the hospital, by phone or other web based 
communication (i.e., zoom, WebEx, skype, blue jeans, go to meetings, WhatsApp, etc.)  
by email, or by digital text based modules that will consist of opportunities to practice 
specific skills (at the patient’s discretion).  Study staff will contact patients to coordinate 
such visits and will prompt them by asking: “Would you like to review or practice any of 
the resilience skills?” [If needed, staff will remind patients of all 4 sessions.  If patients 
are willing, study staff will ask,] “Which one?”

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Finally, in order to practice skills between sessions, all participants with smart phones 
assigned to the PRISM will be invited to download the PRISM app. This platform is 
available in both the iTunes Store as well as the Google Play Store, however, the 
content within the app is only accessible with a password that will be provided by the 
PRISM team.. The app includes digital content of all paper-pencil “cheat sheets” and 
worksheets (see manual in appendix for both paper versions and screen-shots of app).  
Participants will be given access to both types of materials.  Use of the app is optional 
for study participation.  Where relevant (i.e., for participants without a smartphone), we 
will provide iPads to be used in hospital settings.  Note these participants may need to 
establish email account for such purposes if they do not already have one. 
Each site’s interventionist(s) will be responsible for delivering PRISM to their site’s 
participants in the majority of cases. In rare circumstances (e.g., interim coverage for 
unexpected lapses in staffing), trained interventionists from SCH may deliver sessions to 
other sites’ participants pending approval from the site’s IRB. In these instances, the site 
coordinator will be responsible for scheduling the session and setting up a video-
conference using the site’s own HIPAA compliant software (i.e., Zoom, WebEx) for 
session delivery. Thus, no contact would occur between SCH interventionists and site 
participants outside of session delivery. At the start of the session, the site coordinator 
will briefly join the video call in order introduce to the patient and SCH interventionist 
using first names only. Any correspondence between site coordinators and SCH 
interventionists regarding session scheduling will use study ID numbers only. 
9.5 
MEMS cap and adherence assessments.
For patients who are eligible and consent to the optional medication adherence 
monitoring portion of the study, we will use the medication electronic monitoring system 
(MEMS) monitoring device to evaluate real-time medication adherence for oral 
immunosuppressive medications (standard prophylaxis against Graft-Versus-Host 
Disease [GVHD]).  The MEMS system employs a microelectronic technology to record 
actual medication vial openings (date and time) as a measure of dosing.  It is widely 
considered the gold standard of medication-adherence methodology.96,97  
Beginning 2 weeks following the date of discharge from initial HCT hospitalization and 
for the final duration of the remaining 6 months on study, participants will store 
prescriptions for their primary GVHD prophylaxis (typically either tacrolimus or 
cyclosporine), in study-dispensed MEMS bottles and caps.  A patient supply kit 
containing a MEMS cap and bottle will be dispensed to all study participants by the 
institutional RA no more than 7-10 post discharge. The patient will receive instructions 
directing them to put their primary GVHD prescription into these bottles and to take their 
prescription using the MEMS medication bottle.  The patient will be instructed that any 
additional refills of their GVHD prophylaxis required during the study period are also to 
be added to their MEMS medication bottle. When possible, the study RA will meet with 
families in person approximately 2 weeks post-discharge to verify new prescription has 
been dispensed in these bottles and to review procedures.  A study coordinator will 

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contact study participants monthly by phone, email, text or in person to answer any 
questions or concern the patient may be having.
The following instructions will be included in the patient supply kit: 
1.
In the next 1 -2 days, please put your main GVHD prophylaxis medication into 
your MEMS medication bottle. If you are unsure what medicine this is, please 
check with your study team.  
2.
Once you have filled your bottle, before you take your next dose of your GVHD 
medication, please replace the regular cap with the MEMS TrackCap you 
received in your study kit.  
3.
All doses of your GVHD medication should be taken from the MEMS 
medication bottle with the MEMS TrackCap while you are on this study. 
4.
Please take your GVHD medication exactly as your doctor has ordered.
5.
Open the medication bottle ONLY when it is time for you to take your GVHD 
medication.
6.
Close the medication bottle right after taking the GVHD medication.

To refill your GVHD medication while on this study, follow these instructions.  

Only refill your medication when you need to take a dose of your GVHD 
medication!
•
Open the old bottle and take out a dose of medication.
•
Refilled bottle with your GVHD medication using your prescription 
bottle from your pharmacy.  
•
Replace the electronic Trackcap onto the newly refilled bottle of 
your GVHD medication.
•
Please do not refill or open your MEMS cap when you are not 
taking your medicine.
If medications are dispensed in a blister package, if possible, study participants will be 
asked to place blister packages into medication bottles and take as above.  Because 
most AYAs can take tablets, use of liquid formulations will be rare.  However, when 
indicated or requested by patients, pharmacists will dispense oral, crushable tablets for 
compounding.  Those study participants will, however, be asked to open their MEMS 
bottle at the same time as taking their GVHD medication.  Patients will be instructed not 
to open the container unless taking a dose of the medication and to remove only the 
prescribed dose. After the final 6 months of study participation, study participants will be 
asked to return their MEMS track cap to their study coordinator.
9.6 
Data collection schedule for study staff.
Caregiver reported costs of care and medical record data will be collected monthly 
(Figure 3).  Details about staff-data collection are as follows:

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9.6.1
Digital pharmaco-adherence.  Medical record abstraction will include 
prescription details including medication-name, frequency, and dosing.  
9.6.2
Health care utilization.  The Case Report Form (CRF, appendix) will capture the 
following variables through medical records and billing systems: (1) Intervention 
time: visit time related to case management and PRISM sessions; (2) mental 
health utilization: number, location, and duration of formal psychosocial clinician 
visits, psychological diagnoses, number of prescription psychiatric medications; 
and, (3) additional relevant utilization: number of supportive care medications 
(including acute and chronic pain medications and sleep-aids), number of and 
reason for unplanned hospital days, Emergency Department, outpatient clinic 
visits; resource use associated with additional health problems and diagnoses 
such as medical treatments an procedures, additional hospital services, distance 
between home and primary care facility (documented by home zip code), etc.   
9.6.3
Additional covariates. RA’s at each site will prospectively abstract the following 
clinical covariates from the medical record (using study-specific CRFs, 
appendix): the AYA’s diagnosis, GVHD-directed treatments (and modifications), 
and treatment-intensity in the past month.98 These variables were selected to 
capture relevant costs and based on prior evidence that AYA well-being and 
family psychosocial needs affect immediate psychosocial outcome metrics (e.g., 

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psychological distress and quality of life).46,98  In addition, RAs at each site 
collecting biomarker data (i.e., heart rate variability and/or blood samples) will 
abstract additional clinical covariates to provide needed context as to the 
conditions under which the corresponding biologic data were collected. These 
data will only be collected for participants who consented to the HRV and/or 
CTRA optional components of the study. Sites collecting heart rate variability 
(HRV) data will abstract the following clinical information for participating 
patients: cardiac medications, diagnostic cardiac test data, and patient weight, 
height, and Body Mass Index (MBI). Sites collecting blood samples will abstract 
the following information for participating patients: date of conditioning 
chemotherapy and/or radiation start, transplant date, and blood test information. 
9.7 
Resilience in Pediatric Cancer Assessment (RPCA) Survey (both arms):
Patient (and parent) reported outcomes (PROs) will be measured with the Resilience in 
Pediatric Cancer Assessment (RPCA), a comprehensive survey comprised of age-
appropriate validated instruments (Table 5).  The RPCA was designed with AYA and 
parent stakeholders to capture patient-reported outcomes associated with resilience 
resources.30 We have successfully used it in several of our prior studies.29,30,90-92,99 The 
survey includes embedded validated instruments as well as standard demographics 
(age, sex, and race/ethnicity, education, income, number of children in the home).  
The full RPCA survey will be administered to patients and parents at baseline, month 3 
and month 6 (Figure 3).  In order to optimize engagement, parents in both arms of the 
study will be asked to complete the abbreviated Resilience in Pediatric Cancer 
Assessment (aRPCA) at months 1, 2, 4, and 5.  The aRPCA will assess only cost-
consequences, as described below. In the rare case that a patient is their own money 
manager, AYA patients will be asked to complete cost-consequence questionnaires at 
each month in lieu of parents. RPCA and aRPCA surveys will be administered via 
REDCap or pencil-and-paper, depending on participant preference. If administered via 
REDCap, participants will be sent an email containing the survey link. Email language 
will include all text described in the IRB-approved template (see “PRISM BMT Survey 
letter – REDCAP”) though additional personalized text may be included to reflect 
participants’ specific needs. Paper-and-pencil surveys will be delivered in-person or via 
mail. If patients or parents specifically request to opt-out of aRPCA surveys (i.e., cost 
consequences assessments), study staff will no longer administer aRPCA surveys for 
the remainder of the study. In these cases, patients/parents will remain eligible to 
complete RPCA surveys. 
For those on the non-intervention arm of the study, staff will schedule a “study check-in” 
visit to coordinate the aRPCA completion and thank families for their continued 
participation. If patients and parents have not completed any interval study 
questionnaires, we will still invite them to complete the 6 month questionnaire regardless 
of how many intermediate questionnaires they have completed. If patients and parents 

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are reluctant to fill out the full RPCA at 3 month and/or 6 months, we will offer a 
shortened RPCA assessing the primary outcomes only. If patients are still reluctant to 
complete the questionnaire due to length, we will provide a HADS only questionnaire 
option. Patients and parents will be given up to 4 weeks to complete the 6 month 
questionnaire before deemed ‘off study’. 
In both arms of the study, if any participant declines to complete the full RPCA survey 
and/or if participants or family members report participants are unable to complete the 
survey due to illness complications, staff will offer in the following order: (a) an in-person 
(English-speaking, interview based) survey session, and (b) abbreviated version 
(primary outcome only – HADS questionnaire only) of the questionnaire for patients to 
complete.  Only in cases where participants are too ill to provide self report in writing or 
interviews, staff will offer abbreviated versions of the survey for parents to complete as 
proxy respondents. These proxy questionnaires would be the patient questionnaire given 
to the parent to complete on behalf of their child.  In such cases of proxy-completion of 
surveys, staff will note this distinction in the database and proxy-completion will be 
included as a potential confounding variable in subsequent analyses. These options will 
be offered in an effort to collect full data for primary endpoint assessment.   
Participants in both arms of the study will be scheduled for their surveys at the time of 
enrollment and then reminded 1 week and 2 days prior to each survey due-date. 
Participants will be contacted in person, by phone, email, text or mail to receive their 
RPCA/aRPCA surveys. If we have not received a response within a day of initial contact, 
participants will receive up to 4 follow-up phone calls, texts or emails (approximately 
once weekly) within a 28 day window before and after surveys are due.  Follow-up 
surveys not received within 28 days of their due-date will be considered missing.  
Participants will remain eligible for subsequent survey completion and follow-up even if 
surveys are missing and the same procedures will be conducted for each survey due-
date. 
Table 5. Resilience in Pediatric Cancer Survey Domains
Anxiety & Depression: Hospital Anxiety and Depression Scale (HADS)1
Symptom Burden: Memorial Symptom Assessment Scale (MSAS)2 
Quality of Life: PedsQL Generic Core and Cancer Modules (PedsQL)3,4
Hope: Hope Scale5
Resilience: Connor-Davidson Resilience Scale6
Health Utilities: Health Utilities Index100-104
AYA Surveys
Demographics
Proxy Health Utilities (Health Utilities Index)100-104
Costs of Care Checklist
Quality of Life: Medical Outcomes Study Rand Short-Form 368
Anxiety: Generalize Anxiety Disorder Screener (GAD-7)9
Depression: Patient Health Questionnaire (PHQ-8)10
Family Experience Survey: HCAHPS12
Parent Surveys
Demographics

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9.8     RPCA item details
9.8.1 AYA Version (not included in parent surveys)
9.8.1.1
Hospital Anxiety and Depression Scale (HADS).  The HADS assesses 
mixed affective symptoms in patients with serious illness.1  It has been 
validated in AYAs with chronic illness105 as well as AYA cancer survivors.106  
The scale has excellent reliability (α=0.83-0.82).1  It consists of 7 questions 
for anxiety and 7 for depression.  Each is scored from 0-3, for a total range 
of 0-21 points per subscale.  “Caseness” of anxiety and depression is 
defined as ≥8 points, with sensitivity/specificity of 0.8/0.9 for anxiety and 
0.8/0.8 for depression.1  This instrument will be included in the full (non-
abbreviated) RPCA survey as well as the 3 and 6 month shortened RPCA.  
9.8.1.2
Memorial Symptom Assessment Scale (MSAS). The MSAS measures 
the presence, severity, frequency, and extent of bother from 26 symptoms 
with high consistency (α>0.8).2,107  For this study, we will use a version of 
the MSAS that has been previously developed for and used among children 
with advanced cancer.98,108 Likert scales assess physical (pain, fatigue, 
drowsiness, nausea, anorexia, cough, diarrhea, vomiting, itching, skin 
issues, constipation, dysphagia, dry mouth, numbness, sweating, dyspnea, 
and dysuria), and psychological (irritability, sleep disturbance, nervousness, 
sadness, worrying, difficulty concentrating, and image issues) symptoms.  
Total- and sub-scores are calculated as an average, with higher scores 
representing higher symptom burden.  This instrument will only be included 
only in full (non-abbreviated) RPCA surveys.  
9.8.1.3
Pediatric Quality of Life (PedsQL) Generic and Cancer Module Teen 
Reports. The PedsQL 4.0 Generic and 3.0 Cancer Module include 50 
items evaluating HRQOL of AYAs with cancer.  Queries assess physical, 
emotional, social, and school well-being, plus cancer-related pain and hurt, 
nausea, procedural anxiety, treatment anxiety, worry, cognitive problems, 
perceived physical appearance, and communication.  Scales are available 
for teens and young adults,3,4 and have been used successfully with low 
rates of refusal and minimal missing data.109 Items are rated on a 5-point 
Likert scale and total scores transformed to a 0-100 scale with higher 
scores representing better HRQOL. Internal consistency ranges from 0.75 
to 0.92.4  This instrument will only be included only in full (non-abbreviated) 
RPCA surveys.  
9.8.1.4
Hope Scale. The Snyder “Hope” Scale contains 8 hope items plus 4 “filler” 
questions, and measures “the overall perception that one’s goals can be 
met.”5  The instrument was named based on patterns of hopeful thought 
and assesses patient-reported efficacy by assessing  the ability to generate 
a route to one’s goals (termed “pathway” thoughts) and the ability to initiate 
and maintain the actions necessary to reach a goal (termed “agency” 

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thoughts).  Prior studies performed among AYA cancer patients have 
shown that high-hope individuals have improved psychosocial outcomes.  
The instrument has been validated in both adult and pediatric settings and 
is scored on an 8-point Likert scale.  Higher scores imply greater levels of 
hopeful thought patterns.  Cronbach’s alphas for the whole scale range 
from .74 to 0.84.  This instrument will only be included only full (non-
abbreviated) RPCA surveys.  
9.8.1.5
Connor-Davidson Resilience Scale. The Connor-Davidson Resilience 
Scale (CD-RISC) is a reliable and widely used instrument to measure 
inherent resiliency.6 Questions revolve around personal problem-solving 
and approaches to adversity.  The 10-item instrument has high internal 
consistency (Cronbach’s alpha = 0.85), and has been used in diverse 
populations including adolescents, parents and cancer patients.6,110  
Correlative studies have evaluated the scale with other psychosocial 
measures such as psychological distress,111 PTSD,112 and social support.113  
It also has been used in pharmacologic and other intervention studies to 
model modifiable outcomes  Each item consists of a 5-point Likert scale 
(scored from zero to four) for total of 40 points.  The mean score among 
well US adults is 31.8, with higher scores reflecting greater resilience  This 
instrument will only be included only full (non-abbreviated) RPCA surveys. 
9.8.2
Both AYA and Parent Version
9.8.2.1
Health Utilities Index (HUI).  The HUI is a multi-attribute preference-based 
health-status classification system validated in AYA cancer populations.100-
104  The index consists of 15 total queries to assess 2 systems - cognition, 
emotion, fertility, mobility, pain, self-care, and sensation (HUI2); and, 
ambulation, cognition, dexterity, hearing, emotion, pain, speech and vision 
problems (HUI3).  Scoring is based on standard gamble utilities, with 
scores from 0 (health-state preference equivalent to death) to 1 (perfect 
health).  Parents will be asked to complete the survey as a proxy for their 
AYA participant.  Patient data will be used unless unavailable; only in cases 
where patient data is unavailable will parent proxy data be used for data 
analysis.  This instrument will be included in the full (non-abbreviated) 
RPCA surveys as well as the 3 and 6 month shortened RPCAs.   
9.8.2.2
The COVID-19 Impact Questionnaire. (COVID-IQ) This 7-item, self-report 
questionnaire was developed for this study to assess perceived impact of 
the COVID-19 pandemic on AYAs and parents. Items assess worry/anxiety 
related to COVID-19, life events as a result of COVID-19 (e.g., loss of job, 
missed school), lifestyle changes (e.g., social distancing), and known 
COVID-19 symptoms/diagnoses/treatments of self and family members. 
Respondents are invited to provide free text responses for two additional 
items: 1) “What is helping you through the COVID-19 pandemic” and 2) 
“Please tell us about other effects of COVID-19 on yourself, your child(ren) 
and/or your family, both negative and/or positive.” Lastly, respondents are 

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asked to rate the extent to which their responses to other survey 
questionnaires were impacted by the COVID-19 pandemic. This instrument 
will be included in the patient and parent RPCA surveys. 
9.8.3. Parent Version (not included in AYA surveys)
9.8.3.1
Generalized Anxiety Disorder Screener (GAD-7). This 7-item survey is 
commonly used to identify cases of generalized anxiety disorder and to 
assess symptom severity.9,114  Participants are asked how often during the 
last two weeks they have been bothered by each of the 7 core symptoms of 
generalized anxiety disorder. Response options include “not at all,” “several 
days.” “more than have the days,” and “nearly every day,” scored as 0, 1, 2, 
and 3, respectively. Therefore, GAD-7 score range from 0 to 21, with 
scores of ≥5, ≥10, and ≥15 representing mild, moderate, and severe anxiety 
symptoms levels, respectively. Internal consistency was acceptable 
(α=0.89). Inter-correlations ranged from r = 0.45 to r = 0.65. This instrument 
will only be included only full (non-abbreviated) RPCA surveys.  
9.8.3.2
Patient Health Questionnaire (PHQ-8). This 8-item survey is widely used 
among general populations, patients with chronic illness, and in parents of 
children with cancer.10,11,115-118  It is identical to the also widely used PHQ-9, 
with the exception that PHQ-8 deletes a question about suicidal ideation.  
Research indicates that the deletion of this question has a minimal effect 
because self-harm thoughts are relatively rare and this item is the least 
commonly endorsed item on the 9-item survey.  Furthermore, the original 
validation studies of the two instruments demonstrate similar psychometrics 
and identical thresholds for depression severity.  The instruments have 
excellent psychometric properties (α=0.86-0.89).  Each item is scored on a 
4-point Likert scale and the sum (0- 27) indicates the degree of depression, 
with scores of ≥5, ≥10, and ≥15 representing mild, moderate, and severe 
depression.  Scores correlate with functional status and are sensitive to 
behavioral interventions.118,119   This instrument will only be included only 
full (non-abbreviated) RPCA surveys.  
9.8.3.3
Medical Outcomes Study Rand 36-item Health Survey (SF-36). The SF-
36 is the most widely used generic measure of HRQOL among U.S. 
Adults.80  It incorporates 8 concepts: physical functioning, body pain, 
limitations due to physical health problems, role limitations due to personal 
or emotional problems as well as emotional well-being and social 
functioning, energy, fatigue and general health perceptions.  It includes a 
single item regarding perceived change in health.8  Internal reliability ranges 
from α=0.78-0.93.  This instrument will only be included only full (non-
abbreviated) RPCA surveys.  
9.8.3.4
Hospital Consumer Assessment of Healthcare Providers and Systems 
(HCAHPS). This survey is a widely used and standardized tool to measure 
patient and family perspectives on hospital care.12  It has been endorsed by 
the National Quality Forum (NQF) in order to allow for cross-hospital 

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comparisons.   The survey includes a core set of questions that can also be 
combined with customized project- or site-specific items.   For this study, 
we have included a small subset of questions from domains regarding care 
for teenaged patients, communication and child-centered care, and overall 
hospital ratings.  All items are scored on a Likert Scale (for example, to the 
question “During this hospital stay, how often did providers involve your 
child in discussions about his or her health care?” response options include 
“Never,” “Sometimes,” “Usually,” and “Always.”  This instrument will only be 
included only full (non-abbreviated) RPCA surveys. 
9.8.3.5
Patient costs.  A study-specific cost-of-care checklist was adapted from 
consensus guidelines for cost-effectiveness analyses.78  It will be 
embedded within RPCA surveys and query parent-estimates of: (1) direct 
costs: time costs (travel/wait time, time with providers), out-of-pocket 
expenses (gas/travel, other child-care needs); (2) indirect costs:  time-lost 
from vocation or employment (see appendix).   It will be included in the full 
and abbreviated surveys (RPCA, aRPCA and the 3 and 6 month shortened 
RPCA) in order to minimize recall bias and accurately collect monthly 
costing data from then perspective of parent/guardian caregivers. Due to 
recall bias, parents will be able to complete this questionnaire in real time 
over the course of the month. Parents will be given the questionnaire at the 
beginning of each month to have on hand to complete.  If parents do not fill 
it out in real time, they will have the chance to complete in based on recall 
during their monthly visit in their embedded RPCA/aRPCA
9.9 Optional Procedures
9.9.1
Heart Rate Variability Data Collection
HRV will be measured using the Actiheart 5 external device (CamnTech, Inc, UKFDA 
class 2, 510(k) number K052489). The Actiheart 5 is an FDA-approved, lightweight, 
wireless electrocardiogram (ECG) monitor that attaches to a patient’s torso via two 
standard ECG electrodes. Patients who consent to the optional HRV measurement 
portion of the study will be given their Actiheart monitor at enrollment.  A study team 
member (licensed medical provider or CRA with appropriate certification, per site 
requirements) will place the monitor on the patient (left chest) and ensure adequate ECG 
signal acquisition OR a study CRA will instruct the patient (no physical patient contact 
from CRA). The patients will wear the monitor for a 24h period, and then return the 
device to a study team member. The devices will be collected at the next planned clinic 
appointment if outpatient, or the next day if inpatient.
9.9.2
Blood Samples
Whole blood samples will be sent to the University of California Los Angeles (UCLA) 
Social Genomics Core for transcriptome profiling using RNA sequencing.120 The Clinical 
Research Associate will work with inpatient or outpatient staff to obtain subject’s blood. 
A total volume of 5 ml of blood will be collected from subjects at the time of any clinical 
blood draw or intravenous access near the planned study time point. For smaller 

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children, we will follow clinical guidelines regarding volume of blood draws. Blood 
samples needed for clinical purposes will be prioritized over research lab collection.  
Biospecimens (blood samples) will be temporarily stored in secure freezers at Seattle 
Children’s Hospital Research Lab Services (RLS).  The specimens will be labeled only 
with study identification numbers. Blood samples will be stored until 20 samples have 
been collected (anticipate <6 months depending on enrollment), and then will be shipped 
to the UCLA laboratory for analysis. No biospecimens will be banked.
Following quality assurance testing of suitable mass (Nanodrop ND1000) and integrity 
(Agilent Bioanalyzer RNA Integrity Score), mRNA will be converted to cDNA (Illumina 
TruSeq), and >10 million sequence reads will be obtained on an Illumina HiSeq 4000 
instrument in the UCLA Neuroscience Genomics Core. 
9.9.3
Data Collection Schedule
HRV data and/or blood samples will be collected at clinically relevant and study specific 
time intervals where possible (Table 6).  When not possible, HRV and/or blood sample 
data collection will be scheduled at the patient’s convenience, and/or during the next 
scheduled clinical lab draw. .
10.0
Data and Specimen Banking
10.1
Data storage
All pharmaco-adherence, medical record, health care utilization, HRV, blood samples, 
RPCA survey data, and audio transcriptions will be coded and labeled with study 
identification numbers.  All will be stored in original (hard copy) forms in locked cabinets 
(where relevant) and/or password-protected secure databases (for all electronic survey 
data) at Seattle Children’s Research Institute. Upon completion of data collection, SCH 
will transfer the limited dataset to DFCI per the Data Transfer Agreement.  Original 
surveys will be saved at SCH for 10 years or until final analyses are completed, 
whichever occurs last, in order to ensure data quality.  Coded electronically saved study 
data will be banked indefinitely for future use by the group of investigators conducting 
the study and access will be controlled by the PI’s.  PIs will verify that additional 
analyses have IRB approval. Only study staff with human subjects training will have 
access, subject to approval by the SCH site PI, Dr. Taylor.  No data will be withdrawn 
Table 6. Biological data collection schedule
Time Point
T1
(Baseline)
T2
(PRISM session 
#1 OR 1 week 
post enrollment)
T3
1 month 
(survey timepoint)
T4
3 months 
(survey timepoint)
T5
6 months 
(survey timepoint)
24-hour HRV 
Recording
X
X
X
X
X
Blood Sample
X
X
X

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from the study database. Results of initial analyses will be shared with participants if 
participants request on the consent form that they would like a summary of study results. 
10.2
Data and/or Sample Sharing
Data will not be shared outside the group of investigators conducting the study but will 
be fully shared during and after the study with investigators in the group.  When other 
investigators are interested in new analyses, the PIs will verify they have IRB approval to 
conduct additional analyses. Coded study data will be banked indefinitely for future use 
by the group of investigators conducting the study and access will be controlled by the 
PI’s.   Future studies will formally test the dissemination and implementation potential of 
the intervention once its efficacy is confirmed.  Should the intervention be effective, the 
intervention will be made publicly available for use by the broader medical communities 
caring for AYAs with serious illnesses.
11.0
Data Analysis/Management
11.1
 Overview
The primary statistical analyses will be intention-to-treat to avoid confounding by non-
random participant attrition or crossover.  Demographics, clinical characteristics, items 
within the RPCA, adherence data, and costing data will all be summarized at each time-
point using descriptive statistics: frequencies and proportions for categorical variables, 
means and standard deviations for continuous variables, or median and interquartile 
range if distribution is skewed.  All analyses will be adjusted for patient age and site, as 
randomization is stratified by age and site, as well as baseline characteristics clearly 
imbalanced between groups.  Additional baseline characteristics we consider as 
potential confounders include sex, race, and primary language spoken at home.
11.2 Sample Size Determination and Power
Our focus for sample size estimation is the primary outcome (Aim 1): mean HADS 
scores at 6-month observation. In the following table we list minimum clinically important 
differences (MCID) for various outcomes and detectable differences (DD) with our 
proposed sample size. Sample size is based on preliminary data from our Phase II RCT 
suggesting AYA HADS scores are normally distributed with mean score of 11.1 
(SD=6.2).  Assuming 20% attrition, we will randomize 90 AYAs (45 per arm) to obtain an 
evaluable sample size of 70 AYA participants (35 per arm).  This sample size achieves 
80% power to detect a 4.2-point increase   in the mean 6-month total HADS score.  This 
means 35 per arm will provide us >80% power to detect MCID 3.1 in the primary 
outcome HADS. Detectable differences for secondary patient- and parent-reported 
outcomes given this sample size are shown in Table 7.  Sample size calculations have 
limited roles in economic analyses due to wide variability in distribution of costs and 
corresponding to infeasibly large requirements based on traditional inference.121,122  
Economists therefore focus on determining cost-effectiveness, as described above, 
including confidence intervals to reflect the precision of estimates. 
Table 7. Detectable Differences between groups (in primary and secondary aims including patient- or parent- 
reported outcomes measures) given 80% power and 5% Type I error rate

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Aim
Outcome (Instrument)
Population norms
Source
MCID
DD (SD)
1
AYA Anxiety/Depression 
(HADS total)
Mean 11.1 (SD 6.2)
Phase II RCT
3.1
4.2 (6.2)
AYA Symptom Burden 
(MSAS)
Mdn 8.5 (IQR 4.3-14.0)
Published Data98
(not published)
4.9 (7.2)
2A
AYA Quality of Life – 
General (PedsQL 4.0)
Mean 70.9 (SD 17.2)
Published Data123
4.4
11.7 (17.2)
AYA Quality of Life – 
Cancer Specific
Mean 65.3 (SD 16.3)
Phase II RCT
(not published)
11.1 (16.3)
AYA Hope (Hope Scale)
Mean 49.6 (SD 8.3)
Phase II RCT
(not published)
5.6 (8.3)
2D
Anxiety (GAD-7)
2.95 (SD 3.4)
Published Data9
(not published)
2.3 (3.4)
Depression (PHQ-8)
3.3 (SD 3.7)
Published Data10
5.0
2.5 (3.7)
Parent physical quality of 
life (SF-36 PCS)
Mean 50.3 (6.9)
Published Data124
3-5
4.7 (6.9)
Parent mental quality of 
life (SF-36 MCS)
Mean 42.9 (11.9)
Published Data124
3-5
8.1 (11.9)
11.3 
Randomization
The randomization algorithm will be constructed by the study statistician using a 
permuted blocks scheme with randomly varying block sizes, within strata defined by age 
group and sites. Randomized assignments will be administered by a research associate 
using REDCap.   Randomization will be stratified by age (patients ages 12-17 versus 
ages 18-24) and site. 
11.4 Analysis Plan
11.4.1 Primary Outcome (Anxiety and Depression [HADS scores]). Our primary 
outcome is AYA reported total HADS score at 6 months.  Because the amount of 
change depends strongly on the initial score at baseline we will control for 
baseline score as a covariate in the regression. Regression models will be used 
to estimate mean-level differences and 95% confidence intervals comparing 
scores in the PRISM intervention to those in usual care.  The total HADS score 
will be the outcome, and PRISM intervention indicator will be the predictor of 
interest.  Baseline HADS score, age group, site and other unbalanced 
confounders will be covariates in the regression. With this model specification, 
the regression coefficient of PRISM indicator captures the difference in the 
average changes (from baseline to 6 months) for the HADS score between 
PRISM arm and usual care arm. Thus the primary hypothesis can be tested by 
applying the Wald t-test to the regression coefficient of PRISM indicator. The 
same analysis will be undertaken for the domain subscales of anxiety and 
depression (HADS-A and HADS-D subscale scores).
11.4.2 Secondary Outcomes
11.4.2.1
AYA patient reported outcomes. The same analysis as above will 
be undertaken for the secondary outcomes of symptom burden, 
generic- and cancer-specific quality of life, hope, and resilience.  

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11.4.2.2
Cost per Quality Adjusted Life Year (QALY). We will use a cost-
effectiveness framework to evaluate the overall value of PRISM.81  
We anticipate that supportive care and PRISM will be cost-effective 
compared to supportive care alone. The main cost-analyses will 
determine the total, per-patient, 6-month costs of PRISM versus usual 
care. Using Quality-adjusted life years (QALYs) we will  then  estimate 
the incremental cost-effectiveness ratio (ICER) 
Costs will be calculated with a micro-costing approach, multiplying 
resource use by unit costs.80  Resource utilization will be valued 
through the Medical Expenditures Panel Survey125,126 and the 
Healthcare cost and utilization project,127,128 with additional information 
from the Federal Supply Schedule.78,79 For example, PRISM utilization 
will be calculated by estimated cost per visit category (e.g., in-person 
check-in with/without formal session), plus estimated costs of 
intervention delivery (including facilities and overhead).  We will add a 
fixed $50 per patient cost for caseload supervision and information 
support, consistent with prior analyses of collaborative psychosocial 
interventions.129-131  Patient costs will be valued using opportunity cost 
methods and the proxy-good method in sensitivity analyses.132  
We will calculate ICERs to provide information on the incremental cost 
for each additional unit of change in QALYs. Because the goal of cost-
effectiveness analysis is to inform decisions about resource allocation 
and assess intervention value, traditional hypothesis testing is rarely 
utilized.80  Uncertainty in all ICER estimates will be quantified using 
non-parametric bootstrapping and calculation of a 95% confidence 
interval (CI) with Fieller’s method.133,134  We will calculate QALYs with 
standard utility values (preference-based measures of quality of life 
ranging from 0 to 1, defined by the Health Utilities Index).102  
Sensitivity analyses will calculate QALYs with assigned values for 
HADS scores (1.0 for no, 0.8 for mild, and 0.6 for severe anxiety or 
depression) as described previously.135-137  The rationale for this dual 
approach is that preference-based scoring in pediatrics has limitations 
because rapid developmental changes make it difficult to identify 
health attributes (and hence, utility values) relevant to all age 
groups.138  
11.4.3 Parent Outcomes. The same analysis as above (primary outcome and Aim 2A) 
will be undertaken for the parent outcomes.
11.4.4 Patient Outcome Trajectories. We will use descriptive statistics to summarize 
patient-reported outcomes in each study arm at enrollment, 3 months and 6 
months. We will plot individual patient trajectories across all time-points for each 
outcome measure and attempt to identify trajectory patterns (e.g., stable vs. 
temporary or sustained improvement or deterioration) within study groups. We 
will also plot outcome summaries across time by study group to assess between-

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group differences in overall trajectories and variability.
11.5 
Exploratory Analyses
11.5.1 Digitally (MEMS-cap) assessed medication adherence rates will be defined 
as [(# events of MEMS cap opening/# events prescribed)] x 100.  Days when 
oral GVHD medications were held by the prescriber (captured via medical 
record abstraction) will be removed from the denominator, whereas “missed 
doses” will be defined as those where no cap was opened on a day medication 
was prescribed.  Adherence will be calculated on a monthly basis and 
summarized both monthly, and as a 3-month average. 
11.5.2 We will calculate incremental cost consequence ratios (e.g., the cost for each 
unit of improvement in average HADS scores or adherence) using the same 
costing numerators as above with the HADS and adherence change as the 
denominator.  These will be included not as a threshold for cost-effectiveness, 
but as part of a comprehensive evaluation of both costs and consequences of 
the intervention. 
11.5.3
To explore the contribution of different cost parameters to total healthcare 
costs, we will analyze disaggregated costs (e.g., formal-, informal-, and non-
healthcare sector costs) from a payer and societal perspective.78,139  A similar 
analysis will be completed from the societal perspective.  An incremental 
analysis will estimate the arithmetic mean difference in costs between 
intervention and control patients using multivariable generalized linear analytic 
techniques to adjust for variability in outcomes based on baseline 
characteristics.  Sensitivity analyses will model the potential range of cost 
impact based on variable fee-for-service and out-of-pocket expenses
To explore family experience scores, we will conduct descriptive analyses of 
categorical data.  Comparisons will include standard hypothesis testing including 
chi-square tests for frequency data and Kruskal Wallis for non-parametric 
differences in distribution of responses.  
11.5.4
We will explore the relationship between biomedical variables and patient 
reported anxiety and depression through a combination of paired and 
unpaired t-tests, chi-squared (or Fisher’s exact) tests, and linear and logistics 
regression.  DNE will be defined as the number of days from transplant to an 
absolute neutrophil count (ANC) of >500/mm2 for >3 days.  Cumulative 
incidence and severity of Grade II-IV GVHD will be defined by the revised 
Seattle Criteria as documented by the patient’s clinical provider.  HRV will be 
measured in 24-hour increments using both time and frequency domain 
parameters as established by the international Cardiology task force guidelines. 
Means and standard deviations will be compared to published normative data in 
adolescents. CTRA scores will be divided into two groups (above and below the 
median). We will perform multivariable analyses, adjusting for age, sex, 
diagnosis, disease status at the time of transplant, conditioning intensity, and, 

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immunosuppressive medications/GVHD prophylaxis to examine the association 
between CTRA biology and HCT outcomes.
11.6 Additional analyses, confounders, and other considerations.  
We will conduct interaction modeling and subgroup analyses to explore whether the 
effect of the intervention is modified by medical covariates, symptom distress, and/or 
adherence.  The rationale for these subgroup analyses is grounded in prior findings 
suggesting symptoms, adherence, and overall well-being are associated.140
We will conduct a thorough process evaluation that includes: (a) intervention fidelity; 
and, (b) satisfaction queries. Multiple comparisons are a concern since we are collecting 
multiple measures from patients and are interested in several hypotheses.  We minimize 
this problem by specifying a limited number of main hypotheses for each aim.   The 
Benjamini-Hochberg procedure will be used to control the False Discovery Rate criterion 
at α=0.05  to correct for multiple testing in analyses that are not pre-specified.141  
Likewise, in manuscripts and presentations, we will report the number of tests performed 
and interpret results within this context.  
11.7 Missing Outcome Data
While our goal will be to minimize missing data, data may still be missing due to 
patients/families skipping individual survey items, omissions in medical records, lack of 
follow-up, medical complications, or death.  We will quantify the amount of missing data, 
evaluate the pattern of missingness, association of participant characteristics with 
missing data, and minimize bias and increase efficiency in the associations of interest by 
applying appropriate methods to account for missing data.142-144  For example, for 
outcomes where missing at random (MAR) is a plausible assumption, we will use 
multiple imputation or inverse probability weighting, depending on the statistical model 
being considered. For missing not at random (MNAR) data, we will use sensitivity 
analyses.  In all cases, we will assess the robustness of estimates due to assumptions.
12.0
Confidentiality 
12.1 
Data Storage. All information and biospecimens collected for research purposes will be 
coded.  Identifying information (names, addresses and phone numbers) will be used 
initially only to identify potential patients to approach.   The only link between the 
Participant identifiers and their study identifier will be kept on a password protected 
database and in a locked filing cabinet. There are no patient identifiers collected and 
retained for research purposes. Feasibility data will represent only frequencies and 
percentages.  
12.2 
Patient Identifiers within stored data.  No participant identifiers will be kept with or 
included in the study data.  All identifying patient information will be stored on a secure 
database, or in a locked filing cabinet with the study team.  This data will be stored and 

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maintained for a minimum of ten years or until final analyses are completed, whichever 
occurs last, in order to ensure data quality. 
12.3 
Study-wide data management.  Individual sites will be responsible for original source 
data (surveys, Case Report Forms) until study completion.  All such materials will be 
stored in a locked file cabinet or other office with access only to study staff.  Blood 
samples sent to UCLA for analysis will not contain any participant identifying information, 
they will be labeled with study ID only. When sample analysis is complete at UCLA, 
results containing study ID only will be faxed or scanned to the coordinating center for 
electronic storage. Upon study completion (last data collection for last patient), all 
materials will be coded (labeled only with study id) and faxed or scanned to the 
coordinating center for electronic storage.   
As described above, monthly site data collection responsibilities will include monitoring 
of local data completeness and troubleshooting with the coordinating center for data 
completion, if necessary. Per the Data Transfer Agreement, a Limited Data Set will be 
transmitted by Seattle Children’s research staff to external collaborators using a secure 
institutionally-approved method. Any data provided from SCH to Dr. Rosenberg and 
DFCI for oversight purposes during active data completion will also be deidentified. 
Individual site teams will make all study files available during the on-site monitoring of 
the study by the coordinating site. In this instance, PHI will be viewable by the monitor 
for data accuracy but will not be copied or stored. 
When Zoom is used, the following actions will be taken to protect confidentiality and 
privacy:
1.
The latest version of Zoom that is available will be used.
2.
The meeting room will be set to private.
3.
A password/passcode will be required for meeting entry.
4.
The private chat function will be disabled.
5.   The General chat function will be used. Examples of General chat use may include 
sharing approved resources and PRISM app passwords, communicating if there are 
technical difficulties, and the accommodation of specific needs by participant’s 
request (e.g. if a patient has a medical reason that may impact verbal 
communication). 
13.0
Provisions to Monitor the Data to Ensure the Safety of Subjects
13.1
Data collection: 
Data collection will occur at each of the enrolling study sites: Seattle Cancer Care 
Alliance (Seattle Children's Hospital and Fred Hutchinson Cancer Research Center), 
Children’s Hospital Los Angeles (CHLA), University of Alabama at Birmingham (UAB) 
and St. Jude Children’s Research Hospital (SJCRH), with the exception of CTRA gene 

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expression, which will only be collected at the Seattle site. Data collection will consist of 
self-report questionnaires and electronic ECG recordings from HRV monitors. Research 
material collected will be in the form of data from standardized questionnaires, digital 
ECG files, and also from medical record information extracted from the patient’s 
electronic medical record. Protected health information (PHI) is accessible only by the 
site PIs and key study personnel.
13.2
Data Management
Research material collected will be in the form of data from the standardized 
questionnaires, medical record information, digital ECG files, blood samples, and 
electronic MEMs cap medicine adherence data. Protected health information (PHI) is 
accessible only by the site PIs and key study personnel, and the on-site monitor from the 
coordinating site (SCH).  A variety of measures will be utilized to ensure participant 
privacy. Minimal paper records, such as consent forms, will be kept in a locked drawer in 
the site PIs’ research offices. No identifiable patient information will be labeled on the 
surveys, blood samples, or ECG files; all will be identified with a study-specific identifier 
with assigned identifier kept on a password protected encrypted server. Data will be 
stored in an electronic database (REDCap -Research Electronic Data Capture) using the 
participant’s study identifier. REDCap data collection projects rely on a thorough study-
specific data dictionary defined as an iterative self-documenting process by all members 
of the research team. We have conducted the iterative development and testing process 
previously, resulting in well-planned data collection. REDCap servers are housed in a 
data center and all web-based information transmission is encrypted. For the present 
study, we will use the REDCap system managed by the University of Washington 
Institute for Translational Health Sciences (ITHS).  REDCap was developed specifically 
around HIPAA-Security guidelines and is recommended to researchers at various 
institutions by both Privacy Officers and Institutional Review Boards. REDCap has been 
disseminated for use locally and at other institutions and currently supports over 300 
academic/non-profit consortium partners on six continents and over 20,000 research 
end-users (www.project-redcap.org). The REDCap data record may contain some 
identifying information. Subjects will be tracked using their study identifier. The 
identifiable data will be designated as “PHI” in the REDCap database which will allow us 
to exclude access to the identifiable information as necessary.
13.3
Survey data
The study questionnaire (“Resilience in Pediatric Cancer Assessment”, RPCA) and the 
intervention (“Promoting Resilience in Stress Management”, PRISM) may address 
sensitive matters. Participants may be prompted to think about the threat to their life 
posed by their cancer, as well as other difficult topics such as psychological distress, 
grief, bereavement, and health behaviors. The topics to be covered may provoke 
sadness, anxiety, depression, fear or doubt. 
While surveys will be coded to protect anonymity and do not include instruments to 
directly measure suicidal ideation or other self-harming behaviors, they will be reviewed 
within 72 hours for (a) missingness (see 13.4.1 below); and (b) unanticipated immediate 
threats to participants’ or others’ safety. 

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As part of the informed consent process, participants will be made aware of the survey-
review timeline, as well as the fact that confidentiality may be broken in the case that 
providers see an immediate threat to the patient’s or another’s safety. No physical risks 
are expected to arise from the study.
If indicated, referral for consultation will include a direct phone call (or in-person 
consultation) by PI or research team member to recommend further help. This would 
include alerting: a) current therapist (if they have one), and b) their oncology social 
worker. The participant will also be given the phone number to the site’s outpatient 
psychiatric clinic, and county-specific crisis line phone numbers will also be provided as 
needed. 
In the event of other concerns from interventionists and/or other study staff based on 
interactions with AYAs and families, as well as in other cases of concern for patient or 
others’ safety, the same processes will occur, including immediate referrals to the site 
PI, and the patients’ primary medical and social work teams for in-person evaluation or 
referral to the appropriate mental health professional if warranted. After hours, the site PI 
and on-call providers from the medical teams will be notified.  All study-related concerns 
for patient or other person’s safety will be reported as an adverse event (AE) to the IRB 
and Data Safety Monitoring Committee (DSMC, see “Data Safety Monitoring Plan”), 
within 1 week of study staff awareness.  In addition, the PI will review the potential risks 
and reported findings at least once monthly with study staff from all participating sites.  
While this is not a pharmacologic trial and we do not anticipate medical complications, 
sites will nevertheless notify the IRB and DSMC of all participant deaths at the time of 
study renewal (annually).  Unanticipated (non-medical) participant deaths will be 
reported to the DSMC within 1 week with a determination if the event might be 
attributable to the study.  In such cases, the DSMC chair may convene the committee 
and/or suspend the study for additional review (see section 13.5 below).  
13.4
MEMs Cap Medicine Adherence Data
The coordinating center will be responsible for uploading and maintaining the MEMS cap 
medicine adherence data.  After each patient returns their MEMS cap following their 
study completions, the study coordinator will mail the track caps in padded envelope to 
the coordinating center -  Seattle Children’s Hospital Attn: Molly Taylor (1920 Terry Ave. 
M/S CURE-4, Seattle, WA 98101). The site coordinator will upload the data will be via 
the MEMS MAP modem (Aardex Group, Belgium), yielding a record of times and dates 
that the container was opened.  These methods have been used successfully in prior 
pediatric and AYA adherence studies.97,145,146
13.5
Heart Rate Variability Data
Following a 24-hour recording, a study team member will collect the Actiheart monitor 
from the patient (either in clinic or while in the hospital).  De-identified data from the 
device will be uploaded into the Actiheart software (CamnTech, Inc), which will be 
installed on one computer located in the locked office of the study PI.  Data will then be 
transferred to the abovementioned encrypted RedCap database.
13.6
Blood Samples 

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5 mL whole blood will be collected in a PaxGene (PreAnalytiX GmbH) blood tube at the 
time of a planned clinical blood draw. These biospecimens will be labeled with the 
subject’s study ID only (no identifying information) and sent to the Seattle Children’s 
Research Lab Services (RLS) Core (Seattle Children’s Hospital, Seattle, WA) for 
storage. De-identified, batched blood samples will be shipped by RLS to the University 
of California Los Angeles (UCLA) Social Genomics Core Laboratory for analysis.
13.7
Data Collection Procedures/ Internal Site Monitoring plan:
The coordinating center will be responsible for systematic data collection, quality control, 
and data-management procedures including: (1) oversight of ongoing data collection; (2) 
rigorous training and ongoing monitoring of adherence to protocols; (3) regular review of 
questionnaire response rates and missing items to identify and correct problems; (4) 
verification of all data through computerized data entry systems restricting invalid/out-of-
range responses;  (5) at minimum monthly meetings and progress reports to provide 
feedback to study staff concerning difficulties and follow-up to ensure problems are 
resolved quickly, and (6) yearly on-site monitoring of participating sites.   
13.7.1 Survey data: 
To optimize collection, all participant surveys will be available by paper or online 
via the REDCap system, a secure HIPAA-compliant, high-quality data collection 
tool. The rationale for offering both paper-pencil and electronic versions is based 
on our prior experience where participants preferred the former,92 which in turn 
facilitated more complete data collection.  To ensure primary outcome data, we 
will offer an abbreviated survey with only the HADS and HUI for those who do not 
complete all assessments or who request to drop out.  To ensure data quality, a 
RA will review RPCA surveys within 72 hours of their completion for missing 
fields and call participants to clarify and query/complete individual missing items 
verbally.  
13.7.2 MEMS caps: 
One to two weeks following discharge from the initial HCT and the day after any 
subsequent hospitalizations, an RA will contact the family by phone to review the 
MEMS-cap system and, where relevant, confirm the MEMS-cap is being used.   
Where indicated, to identify obstacles and solutions to its use. 
13.7.3 Medical record data:  
RA’s will collect and upload CRF data monthly.  To ensure reliability and validity 
of abstracted medical record data, we will use our current methods for training 
and quality control, including guided practice abstraction and independent 
abstraction with reconciliation by a trainer.  A 10% random sample will be dual 
abstracted.  A RA assignment will monitor and reconcile case report forms with 
RedCap data once monthly.
13.7.4 Heart Rate Variability monitors:

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Staff investigators and RA’s will be trained on recognizing adequate signal 
acquisition on the Actiheart monitors when the patient initially has the device 
placed.  If there is suboptimal recording identified, the team member placing the 
device will be able to recognize in real time and make appropriate adjustments to 
the equipment based on Actiheart user manual suggestions.
13.7.5 Blood Samples: 
Following quality assurance testing of suitable mass (Nanodrop ND1000) and 
integrity (Agilent Bioanalyzer RNA Integrity Score), mRNA will be converted to 
cDNA (Illumina TruSeq), and >10 million sequence reads will be obtained on an 
Illumina HiSeq 4000 instrument in the UCLA Neuroscience Genomics Core. 
Reads will be mapped to the RefSeq human genome (hisat2/stringtie) to 
estimate gene transcript abundance counts per million mapped reads.
13.8
Safety and Compliance Monitoring
This is a small multisite clinical trial of a supportive care intervention that presents no 
more than minimal risk. As such, data monitoring will be primarily carried out by the Lead 
RA at the coordinating site (SCH) and a small, external Data Safety Monitoring 
Committee (DSMC). 
13.8.1 Data and Safety Monitoring Plan
Safety monitoring will be the responsibility of a 4-member Data Safety and 
Monitoring Committee (DSMC) composed of professionals across the country 
representing different disciplines and expertise (see table below). All members are 
independent of the protocol.  The committee will be convened at the beginning of 
the study and then twice annually via conference calls, to provide input and 
guidance on the study evaluation and intervention protocols, including quality 
assurance and safety issues related to the protocols, as well as data handling 
activities. As above, in the event of an unanticipated patient death, the committee 
may convene an ad-hoc session and/or suspend the study to assess patient risk 
and/or necessary revisions to the protocol.
13.8.2 Data and Safety Monitoring Committee 
Member Name (Title)
Discipline
Research Expertise
Chris Dvorak, MD (Chief, Division of Pediatric Allergy, 
Immunology, and Bone Marrow Transplantation, 
University of California at San Francisco)
Pediatric Hematology/Oncology 
and  Hematopoietic Cell 
Transplantation
Hematopoietic Stem Cell 
Transplant, Cancer Control 
and Supportive Care
Kristina K. Hardy, PhD (Associate Professor, Depts. of 
Psychiatry and Behavioral Medicine and Pediatrics, 
George Washington University School of Medicine)
Pediatric Psychology and 
Behavioral Medicine
Psychosocial oncology and 
behavioral intervention 
development
John Salsman, PhD (Associate Professor and Director 
of Clinical Research in Adolescent and Young Adult 
Oncology, Dept. of Social Sciences and Health Policy, 
Wake Forrest University School of Medicine)
Adolescent and Young Adult 
Psychology
Adolescent and Young Adult 
health psychology, patient-
reported outcomes research
Corinne Summers, MD (Committee Chair, Assistant 
Professor, Dept. of Pediatric Oncology, University of 
Washington School of Medicine)
Pediatric Hematology/Oncology 
and Hematopoietic Cell 
Transplantation
Hematopoietic Stem Cell 
Transplant

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13.8.3 Monitoring study safety.  
DSMC members will provide input and feedback to the PI and Co-investigators, 
via e-mail and conference calls, related to (a) accrual rate, (b) study eligibility 
determination issues, (c) data completion rates including conformance with 
informed consent requirements, (d) intervention fidelity indicators, (e) adverse 
events, and (f) compliance with data management procedures. The lead 
statistician will oversee the summarization of online data to evaluate data 
completeness and protocol adherence. The Lead CRA will also send monthly 
reports summarizing recruitment and other site specific data (such as indicators 
of intervention delivery, occurrence of adverse events, and conformance with 
IRB requirements). 
The committee will also receive information on questionnaire data, presented for 
the participants overall rather than by study group. This study will not have pre-
set stopping rules, but the DSMC will have the option of requesting the data be 
un-blinded and considering altering the study or stopping the study early.  
Although the full committee will meet twice-yearly, the chair will be free to 
assemble the full committee at any time if the chair believes it is important. 
Because committee members may be located at various sites, the committee 
meetings may be conducted by phone. 
Data safety monitoring for the intervention will focus on assuring that subjects 
are not experiencing any significant or unexpected distress and that they are 
satisfied with the intervention components; we will monitor all complaints about 
the study.  We do not anticipate stopping the study early for efficacy or harm, 
but the DSMC will have the option to consider such action in the event of a 
highly unexpected result. The DSMC will review the draft questionnaires to be 
sent to subjects and review any complaints that may be received from patients, 
family members, clinicians, or others.  We do not anticipate any external factors 
such as findings from ongoing trials that will affect the safety of participants or 
the ethics of this research study.
13.8.4 Identification, review and report of adverse events and unanticipated 
problem. 
Adverse events information will be collected at all assessment points and 
recorded on standard forms. We will collect information on all potential types of 
adverse events. Consistent with NIH, and the sites IRBs policies, adverse 
events will be promptly reported in writing to the NIH, individual IRBs, and the 
DSMC chair. The DSMC will modify or stop the study if any such complaints 
represent a legitimate concern about the study procedures or methods.  
13.8.5 Compliance with monitoring requirements. 

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Compliance with the monitoring plan will be ensured through the Lead RA’s 
close supervision. The Lead RA will hold no less than monthly calls with the 
sites to monitor recruitment and protocol adherence. Site RAs will gather 
required information on an ongoing basis and send monthly written reports to 
Lead RA. The Lead RA will schedule yearly on-site monitoring visits as the 
coordinate site for data completeness and accuracy. Site RAs will assist in 
providing on-site monitors with appropriate access to all study related charts and 
databases during the visit. 
13.8.6 Assessment of relevant external factors. 
Given the characteristics of the intervention, it is unlikely that a breakthrough 
result from another study will change the course of this study. 
13.8.7 Interim analysis plan. 
An interim analysis to assess for safety and missingness will be lead by the 
study statistician after half of the targeted sample size of participants have 
reached the primary endpoint. The DSMC will determine a priori stopping rules 
occurrence of serious events, including (but not limited to) stopping the study for 
efficacy if interim analysis is significant. 
14.0
Withdrawal of Subjects
14.1
Plan for Non-Responders
Response to the intervention will be determined upon study completion (not in “real-
time,”).  All participants, including those on the intervention arm, will continue to receive 
usual care, including as-needed referrals for professional psychology services. 
14.2 
Early Withdrawal of Subjects
All participants may choose to withdraw from the study at any time.  We will track date of 
discontinuation and request a brief reason to be recorded for tracking purposes.  In the 
event of serious medical complications (or death) precluding participation, participants 
will be censored after 2 months of missing data. In all other cases (non-completion of 
surveys without serious medical complications or death), staff will continue to request 
surveys until 2 months following the 6-month endpoint, as described above.   
14.3 
When and How to Withdraw Subject
In this intention-to-treat analysis plan, all participants who fill out a baseline survey will 
be included in analyses.  As above, withdrawal will be determined by study staff only in 
the event of medical complications or death.  
14.4 
Data Collection and Follow-up for Withdrawn Subjects 
Unless explicitly indicated by participants who withdraw their consent, baseline data for 
all eligible patients will be maintained and utilized in analyses.  

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15.0
Risks to Subjects
The intervention (“Promoting Resilience in Stress Management”, PRISM) and our surveys may 
address sensitive matters in that it they patients to identify stressors and negative thoughts.  
Adolescent and young adult participants may be prompted to think about the threat to their life 
posed by their cancer, as well as other difficult topics such as suicidal ideations, sexuality and 
substance abuse.  During the coming together session and/or while completing surveys, 
parent(s)/caregiver(s)/spouse/significant other may be prompted to think about the threat to their 
child’s/significant other’s life by cancer.  The topics to be covered may provoke sadness, 
anxiety, depression, fear or doubt for AYAs and/or their parent(s)/caregiver(s)/spouse/significant 
other.  Administrators of the intervention will be trained to inform the patient’s primary social 
work and/or medical teams if the patient and/or parents/guardians/spouses/significant others 
endorses thoughts of self-harm or harm to others. As part of their informed consent process, 
participants will be made aware of this policy, as well as the fact that confidentiality may be 
broken in the case that providers see an immediate threat to the patient’s or another’s safety.  
Patients who participate in the optional HRV measurement component of the study may 
experience some mild physical discomfort or skin irritation associated with wearing the ECG 
monitor.  The risk is minimal, as this process is identical to standard ECG measurements 
obtained for clinical purposes, of which all participants will have undergone.  Minimal physical 
risks are expected to arise from the study, primarily related to the optional blood sample 
component. All patients undergoing HCT will have a central line, and blood samples will be 
drawn from the central line as the default; peripheral IV blood draws will only be performed if the 
patient does not have a functional central line. There would not be an additional “poke” to draw 
research blood from a participant. Risks associated with blood draw include slightly prolonging 
the length of another planned blood draw, and rarely fainting or infection. The research blood 
samples will be drawn at the same time of clinical indicated blood draws so that these risks are 
not increased.  Blood draws will be performed by trained personnel who are experienced in 
working with children and familiar with processes of lab draws from central lines, and the 
challenges of drawing blood from this population.
The particular type of genetic testing to be performed using the blood samples will not pose any 
additional risks to subjects. The CTRA analysis is not a traditional genetic test (it does not test 
for the presence or absence of certain genes or mutations that might confer any kind of risk to 
the patient).  It is testing how “turned on” or “turned off” certain ubiquitous genes are in a 
particular subject, but does not provide information on the subject’s underlying DNA makeup. 
The results of this analysis will not have any bearing on a participant’s genetic risk factors for 
developing certain diseases.
The primary risk to participants will be concerns about confidentiality, and stress of discussing 
the topic of their or their child’s/significant other’s cancer experience. While the potential risks to 
participants are low, we will take steps to ensure that all potential risks are handled 
appropriately as described below.
Due to the nature of the PRISM intervention, all staff and participants will be unblinded from the 
time of randomization. 
We recognize the unique risks of data collection for an AYA population. The major risk is 
compromise of personal data. Thus, confidentiality procedures for all data will be a priority for 

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this study.  All data will be maintained on secure computers or in locked offices at Seattle 
Children’s Research Institute (data collection center).  The study results will be kept for at least 
ten years or until final analyses are completed, whichever occurs last, in order to ensure data 
quality.  The subject’s consent to use or share PHI does not expire.  Access to the building 
where the study data will be kept at Seattle Children’s Research Institute limited to authorized 
personnel.  The Lead RA and other researchers involved in this project has years of experience 
and has received ongoing training at Seattle Children’s Research Institute on confidentiality as 
well as HIPAA confidentiality standards.  Our and other previous trials have kept their data at 
Seattle Children’s Research Institute in the recent past, and the security and confidentiality of 
the data have never been compromised
15.1
Alternatives:  Patients may opt not to participate in the research. Their care will not be 
affected in any way should they decline participation.
16.0
Potential Benefits to Subjects
We hypothesize that patients who receive the intervention will have diminished psychological 
distress and greater quality of life.  We also hypothesize that parents/caregivers/significant 
others/spouses  will benefit similarly from their child’s/partner’s participation because prior 
experience in pediatric cancer studies suggests it is personally important for some patients and 
caregivers to share their perspectives, challenges and growth experienced during their cancer.  
However, there may be no direct benefit for participating in this study if our hypotheses are 
wrong.   More broadly, information gained from this study may heighten the understanding of 
the AYA cancer experience and elucidate strategies that foster resilience and promote better 
quality of life in this group of high risk patients.  These strategies could be extended to the care 
of other AYA patients facing non-cancer-related life-threatening illness. This research has the 
potential to contribute to the research base concerning the promotion of optimal quality of life 
and mental wellness for all AYA patients.   
17.0
Vulnerable Populations
17.1 
This Study includes the following vulnerable populations:
17.1.1 Individuals who are not yet adults (children, teenagers): Pediatric patients with 
serious illness are at risk for poor outcomes and may benefit from resilience-
enhancing interventions in the future. We justify the inclusion of children in this 
project because the implementation of those interventions requires feasibility 
information and patient feedback. This study will provide those crucial data.  
Patients enrolling in this study may, in fact, benefit from the intervention; 
however, at the time of consent, we will ensure that all patients and families 
understand the objective of this study are to test the feasibility of this intervention 
such that it may be used prospectively in the future (see risks/benefits above). 
17.1.2 Pregnant women: There is a chance that a parent/caregiver/spouse/significant 
other of a patient participant is pregnant and therefore could participate in the 
survey and/or ‘coming together’ portion of this study.  This study does not involve 

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interventions/invasive procedures to the woman or fetus and does not involve 
fetuses or neonates as subjects.
17.2 
This study will not include the following populations either because they do not meet 
inclusion/exclusion criteria of being physically or cognitively able to participate in in depth 
interviews, or because they are anticipated to have inconsistent presence at the 
bedside, suggesting inconsistent participation in said interviews.  
17.2.1 Prisoners 
17.2.2 Cognitively impaired adults
17.2.3 Wards of the state
18.0
Community-Based Participatory Research
N/A
19.0
Sharing of Results with Subjects
1.6.1
Following completion of the study, a written summary of the main results will be provided 
to all interested participants.
There are no plans to return results from the CTRA genetic analysis to participants, as 
this does not relate to their underlying genetic makeup or hereditary risk for disease.
20.0
Setting
1.6.1
Patients will be identified and recruited at either at SCCA or at SCH. See section 23 for 
specifics. 
1.6.2
Study visits may be done in person at SCH in the inpatient room or in the outpatient 
clinical research center or at SCCA on the 6th floor pediatric transplant clinic, or via 
phone or other web based communication (i.e., zoom, WebEx, skype, blue jeans, go to 
meetings, WhatsApp, etc.). 
20.3
There will not be an involvement of any community advisory board.  
20.4 
No local research will be conducted outside of SCH or SCCA.
21.0
Resources Available
21.1 
Interventionist Training and Fidelity.  PRISM has been standardized through the 
creation of comprehensive protocols for those who implement it.  Session-by-Session 
details are provided in the PRISM manual; on outline of each section is listed in Table 1.  
All interventionists undergo at least 4hours of in person training including role-playing 
and progressive mastery of intervention materials.  The fidelity of sessions 1-4 will be 
systematically assessed via audio-recording.  The PI or supervising team member at 

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Seattle Children’s will review the first of each 5 sessions for each interventionist, and 
score them for fidelity using a standardized tool (see appendix.). After the first 5 
sessions are reviewed for each interventionist, one of each 5 subsequent sessions will 
be randomly selected to be monitored for fidelity.  Interveners will receive feedback 
regarding adherence to protocol and approach will be refined with additional training, if 
needed.   
21.2 
Based on the estimated number of AYAs receiving allogeneic or autologous HCT for 
treatment at the study sites, there will be enough patients to meet study enrollment 
goals.
21.3
Refer to ‘Table 4’ for the Timeline of conducting and completing the research. 
21.4 
The PCAR team works closely with the Hematology/Oncology medical and social work 
teams if outside resources or needs arise. 
21.5
CTRA Gene Expression Profiling. Transcriptome profiling and related bioinformatics 
analyses will be conducted by the UCLA Social Genomics Core (Directed by Dr. Steve 
Cole, study consultant). This Core will conduct global gene expression profiling using 
RNA sequencing and report results back to the coordinating institution.
22.0
Prior Approvals
NIH NCI/R01 CA225629-01 was reviewed by the designated NIH study section. 
23.0
Participant Incentives
All active patient participants will receive three installment payments in the form of a $25 gift 
card during the 6-month duration of the study. Patients will be paid one installment of $25 for 
each RPCA survey (baseline, 3-months, and 6-months), for a total of up to $75 for participation.
Throughout their participation on the study, AYA participants will receive small, non-monetary 
items (i.e., a pen, lanyard, tote bag, etc.). Parent/guardian participants will also be offered non-
monetary items (PRISM paraphernalia such as pens, bags, stress balls, mugs, etc.) but no gift-
cards. AYA participants who complete both the baseline and 6-month surveys will also be 
entered in a raffle to win an iPad. At each site, raffles will take place after 10 participants have 
completed all study procedures. Each participant in the raffle will therefore have 10% chance of 
winning an iPad. 
24.0
Use of Social Media
We will not use social media for this study. 
25.0
Local Number of Subjects
We anticipate enrolling 50-60 patients locally in the 3 year study duration (Table 3). 

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26.0
Provisions to Protect the Privacy Interests of Subjects
The study team will use a private room to discuss potential participation and the use of an 
intermediary (as needed) if the subject does not know the researcher. Emphasis will be made to 
ensure that subjects know that not participating will not impact patient care.
The study team will warn the participant of the possibility of sensitive subject matter before the 
session. The study team will be sure to emphasize to the participant that this study is completely 
optional and the participant has the right to not answer any questions that they feel 
uncomfortable with, that they can withdraw their participation at any time, and that their refusal 
to participate in this research will not impact their care.
The study team will have access to any patient/participant information that could pertain to study 
participation or that has an influence on how a participant participates.
When possible, texting participants will occur on a secure, HIPAA-compliant platform. If a 
HIPAA-compliant platform is not available or allowable per specific site restrictions, research 
staff will not include PHI in texting communications with participants and families. Depending on 
the texting platform used, subjects may be able to send text messages back to the study team. 
Any texting platform used (depending on local site requirements) that allows research staff to 
receive text messages from subjects wsill be HIPAA compliant and will protect all information 
received from subjects.  
27.0
Compensation for Research-Related Injury
There is no compensation for research-related injury.
28.0
Economic Burden to Subjects
We strive to complete these visits with patients while they are already at the hospital. As above, 
if explicitly requested, intervention sessions may be conducted via phone or other web-based 
communication (e.g., zoom, WebEx, skype, blue jeans, go to meetings, WhatsApp, etc.)  or via 
phone.  
Patients and families will be asked if they would like to receive text messages from the study 
team for study participation coordination (e.g., enrollment, survey reminders, intervention 
session scheduling, payment). Standard text messaging rates from mobile phone providers may 
be incurred. The study team will inform patients and families of potential charges in the consent 
conference and give them an opportunity to opt out to avoid potential charges.
No additional study visits will be scheduled for study conduction purposes alone (all visits will be 
conducted in conjunction with other medical visits).  It should be noted, however, that one of our 
objectives is to determine economic burdens associated with the intervention and study 
participation.

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29.0
Consent Process
29.1 
We will request a waiver of consent for screening purposes for this study and a waiver of 
documentation of consent for study enrollment in cases where in-person consent 
conferences are not feasible. This will be done so that CRAs may identify potential and 
eligible patients prior to their scheduled clinic visits and to ensure that recruitment is 
possible whilst protecting participant safety.  
29.2 
Consent Conferences. The consent meeting between the CRA and eligible participants 
(with parents if applicable) will include an explanation of the study in developmentally 
appropriate lay-language.  All AYA participants will provide either written informed 
consent (if aged 18 years or more (or assent (if <18 years-old). Parents of teens (<18 
years-old) will provide written informed consent. For patients/families who are screened 
and provide verbal interest by phone, the written consent form may be mailed for receipt 
and review prior to enrollment.  As described in the inclusion/exclusion criteria above 
(Section 3), participants must speak English fluently; however, they are eligible if English 
is not their primary language spoken at home (or if it is not their first language). In cases 
where parent consent is required and parents do not speak English fluently (or prefer 
another language), all conferences will be held in the presence of a trained medical 
interpreter either in person or via phone interpreter.  All participants and parents will be 
provided an opportunity to read the consent/assent form in their preferred language 
(English or Spanish), to ask questions about the study and have those questions 
answered by the research team member before deciding about study participation and 
signing the consent/assent form.   Parental permission for study participation will be 
obtained first then patient assent will be obtained for all patients 12-17 years of age.  If a 
patient indicates that they do not want to participate in the study that non-assent will 
override the parent’s permission and the patient will be recorded as a refusal.  The 
research team member will redirect any parent who attempts to convince their child to 
participate in the study and remind them of their child’s right as a potential research 
participant to refuse participation without coercion.  Consent to study participation will be 
obtained from patients 18 years of age and above. The CRA will emphasize to all 
patients and parents in developmentally appropriate lay-language that being in the study 
is their choice that they may choose not to participate or may change their mind at any 
time and it will not affect how their nurses or doctors care for them. 
When the consent conference is conducted via phone/video, those who agree to 
participate will complete an electronic consent form via the REDCap database using the 
REDCap e-consent framework. Study staff may also email or mail a copy of the consent 
form to subjects if requested. The body of the consent form will be identical, whether on 
paper or in REDCap. A link to the consent form will be e-mailed to participants prior to 
the phone/video consent conference. Study staff will answer any questions about the 
study, and those who agree to participate will provide an electronic signature, date, and 
time on the REDCap form to indicate their consent. The REDCap e-consent framework 
allows participants to create an electronic signature using their cursor and provides a 
timestamp. This framework also automatically generates an extra certification page for 
participants to confirm the correctness of their responses before submitting and stores a 
static copy of their responses as a PDF in the study’s file repository. Subjects will also 

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be prompted to download a copy of their signed consent form from REDCap or study 
staff can e-mail the signed form if requested. After the participant has completed the e-
consent form, the RA will immediately complete a corresponding REDCap form that 
includes: a) the names of the patient and parent (if applicable); b) the name of the 
person obtaining consent; an attestation that the subject agreed to participate, that all 
risks and opportunities of the study were explained, and that the subject had adequate 
opportunity to have their questions answered; and c) the RAs electronic signature and 
corresponding date/time. If an interpreter is used, the name of the interpreter will also be 
documented.
For eligible patients who are visually impaired, the font size on consent forms and other 
documents will be enlarged according to patient preferences. If eligible patients with 
visual impairment cannot read large print text, the consent materials will be explained to 
the subject in the presence of an impartial witness who observes the entire consent 
process. In that case, sufficient time will be allowed for questions to be asked and 
answered, to ensure that the subject comprehends the consent information. The 
presence of the witness will be documented in the chart note and on the consent form.
If participants request for a PDF of the consent forms to be emailed, participants may 
print/sign/scan the form and return to the RA; if mailed, a return envelope will be 
enclosed so participants can sign and return the form. Once forms are received, the RA 
will sign and date, as well as note the date which the phone consent conference took 
place. 
In all cases, RAs will create a consent process note for the EMR. Included in this note 
will be the date of the consent conference, the names of the patient and parent (if 
applicable), the name of the person obtaining consent, the fact that the subject agreed to 
participate and that all risks and opportunities of the study were explained, and that the 
subject had adequate opportunity to have their questions answered. If an interpreter is 
used, the name of the interpreter will be documented.
A separate consent will be obtained from parents/guardians who choose to participate in 
the parent portion of the study, meaning they will be completing their own study 
questionnaires and will be disclosing their own financial and quality of life information in 
surveys. In addition, parents/caregivers/spouse/significant other may provide an 
addendum to the AYA consent/assent to acknowledge that they may participate in the 
‘Coming Together’ portion of the study. Parents/guardians may elect to participate in 
either or both of these study components (i.e., still be involved in the ‘Coming Together’ 
portion of the study and not want to complete questionnaires and visa versa). If 
requested by the AYA, other individuals (i.e., other parents/caregivers/spouse/significant 
other) will also provide an addendum to the AYA consent/assent if they may participate 
in the ‘Coming Together’ portion of the study. There will be a separate addendum to the 
consent form for the optional HRV and blood sample (CTRA) measurement components 
of the study.  Parent consents and both consent addendums will be presented to families 
following either the in-person or e-consent methods described above.
29.2.1 Non-English Speaking Subject:

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Patients who speak English but have non-English speaking parents will be 
eligible to participate.  Procedures for screening, approach, and enrollment of 
these families will be similar to above, except as follows:
29.2.2 For Spanish Speaking Parents:
For patients < 18 years-old: Spanish-English translations of the consent and 
assent forms will be provided for parents during discussions of the study and 
consent conferences and all discussions will occur with trained medical 
interpreters.  
29.2.3 For patients 18 years and older: 
Spanish-English translations of the consent will be provided for parents during 
discussions of the study and consent conferences at patients’ requests.  
Likewise, if patients wish their parents/caregiver/spouse/significant other to 
participate in session 5, “coming together,” parents will be invited to sign a 
Spanish version of the consent.  All discussions involving Spanish (non-English) 
speaking parents will occur with trained medical interpreters.  
29.2.4 For all patients: 
Session 5 (“coming together”) will be offered in the presence of a Spanish 
interpreter.  All other 1:1 sessions will still be conducted in English with English-
speaking, trained interventionists.  
29.2.5 For Other Non-English Speaking Parents, on a case-by-case basis:
Discussions of study will occur with interpreters in the appropriate language.  If 
families and patients are interested in participation, informed consent forms 
would be translated into the native language of the parent.
Everything pertaining to Spanish speaking parents would be the same for other 
non-English speaking parents except that discussions, conferences, and Session 
5 would be in the native language of the parent. 
29.3 
If patient is still actively on study, however, patient is no longer coming to clinic on a 
regular basis and turns 18 years old or needs to re-consent due to a modification with 
the protocol (or other cause), study staff will email/mail the consent to the participant and 
will call the participant (and parents if applicable) and go over study changes.  If emailed, 
participants may e-sign the consent form via REDCap. If mailed, the mailing will include 
a pre-paid return mailing envelope so the participant can sign and return to return to 
study staff. The study staff will make note of the date of the re-consent conference.  
When the participant/parent-signed form is returned the researcher will then sign and 
date it with the current date.  He/she will add a notation that the actual consent 
conference took place on the date noted via telephone.  Similarly, if participants move 
away from a study center, staff will query their continued interest in study participation 

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and offer all study activities remotely via phone or other web-based communication (i.e., 
zoom, WebEx, skype, blue jeans, go to meetings, WhatsApp, etc.) to encourage 
continued participation. Additionally, staff will ask that participants provide a contact 
number or email of their new clinical team such that issues of safety can be 
communicated. Per the Certificate of Confidentiality, patients do not need to sign a 
Release of Information for us to contact their provider in issues of safety to themselves 
or others. 
29.4 Waiver of HIPAA for Recruitment and Alteration of HIPAA 
29.4.1 Provide protocol specific findings justifying this determination: The waiver of HIPAA 
Authorization is being requested for preliminary screening purposes.. Preliminary 
screening procedures are minimal risk; they include a basic review of the patient’s 
medical records to identify whether or not the patient meet basic eligibility 
requirements. In addition, we are requesting an alteration for cases in which it is 
necessary to conduct consent remotely (via phone or video-conference) because 
we cannot approach eligible patients in-person due to patient safety concerns (e.g., 
during COVID-19 pandemic). Many of our participants are immunocompromised, 
and there will be many cases unrelated to or after the COVID-19 pandemic in 
which it would be much safer to approach patients remotely (e.g. when staff are ill, 
when participants are receiving immunosuppressing treatment, when participants 
are very ill). In these cases, we will follow remote consent procedures outlined 
above, and patients/parents will indicate their willingness to participate both 
verbally and via digital signature on the REDCap forms. In-person approaches and 
consent conferences will be prioritized when they are possible, and in those cases 
written signatures will be obtained. Research coordinators will collaborate with the 
site PIs to regarding instances when remote consenting is necessary. Site PIs will 
make the final determination as to when remote consenting is appropriate.     
29.4.2 The research could NOT practicably be carried out without the waiver or alteration. 
Provide protocol specific findings justifying this determination:  We need to have 
the waiver of HIPAA for screening in order to determine potentially eligible 
participants for this study. If we did not confirm eligibility with the clinicians giving 
care, confirmation of eligibility would be dependent upon the patient and parents.  It 
is likely that they would be able to confirm the eligibility criteria but there is the 
possibility that some may not be able to do so for all of the study criteria. It is also 
possible that they may be uncomfortable being asked to confirm the eligibility 
criteria or wonder why it is that they are being asked to do so. We need this 
alteration to be able to consent participants in cases where in-person consent 
conferences may pose risk to the patients, particularly within this 
immunosuppressed, high-risk population. The bone marrow transplant patients we 
are attempting to enroll are highly immunocompromised, with a much higher risk 
for infection by a multitude of transmissible illnesses, and these patients are 
susceptible to substantially worse symptoms and outcomes from such illnesses 

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than a person of average health. For example, as of Spring 2020, the COVID-19 
pandemic has significantly impacted our ability to approach patients and conduct 
consent conferences in person; therefore, without this alteration enrollment in this 
study is not feasible for the foreseeable future. Furthermore, the COVID-19 
pandemic has led us to revisit our previous practices for in-person consenting, and 
determine that, in order to protect patient safety while still giving all eligible patients 
the opportunity to participate in this potentially beneficial research, we need the 
option to enroll patients remotely. In this case, it is currently unclear when this 
pandemic will truly end and could take years for an acceptable measure of safety 
to be restored to our community; furthermore, even once the COVID-19 pandemic 
has resolved there are other potential circumstances that could similarly mitigate 
our ability to approach in-person (e.g., a bad flu season). Thus, this alteration is 
crucial to protect the health of potential research participants while still furthering 
this important research.
 In addition, both of our previous procedures for remote consent conferences are 
no longer feasible in this circumstance, as follows: 1) When a remote consent 
conference was requested by patients or families, we had previously mailed 
consent forms prior to a phone consent conference and requested that families 
sign the forms and return via mail. However, during this unique time, families of 
individuals in our target population are likely exercising extreme caution to protect 
their at-risk child’s health, meaning many may prefer to avoid sharing of physical 
documents via mail. Furthermore, requiring families to return documents via mail 
may pose additional risk and burden as they will need to leave their homes to 
locate mailboxes or visit the post office. 2) We had also previously e-mailed 
consent forms to families and requested that they print, sign, scan and return to us 
via email. However, we have found that this option is very often not doable for 
families in this population as it requires them to have access to a printer and 
scanner, which the majority do not (e.g., families not living at home, when the AYA 
in inpatient, etc.) Therefore, in order to continue to recruit for this study whilst 
ensuring patient safety and minimizing any burden or stress on families, providing 
an electronic means for families to review consent forms and indicate willingness to 
participate (via digital signature) is necessary. 
29.4.3 Whenever appropriate, the subjects will be provided with additional pertinent 
information after participation. Provide protocol specific findings justifying this 
determination: Study participants will be provided with any additional information 
that may become known during the course of the study which may influence their 
decision to be in the study.
29.4.4  Waivers for participants who turn 18: 
We will re-approach and consent participants if they turn 18 while they are still 
actively participating in the study.  However, we request the waiver of consent for 
patients that turn 18 if no further data collection and study related activities are 
occurring, as their data is limited to the continued use of existing data. 

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29.5 Subjects who are not yet adults (infants, children, teenagers)
Consent/assent will be obtained for all patients 12 years-old and older (written assent for 
those ages 12-17, and written consent for those 18 years and older).  These consent 
conferences will be documented in the patient’s medical record.  If a patient indicates that 
he or she does not want to participate in the study, that non-assent will override the 
parent’s permission and the parent will be recorded as a refusal.  The research team 
member will redirect any parent who attempts to convince their child to participate in the 
study and remind them of their child’s right as a potential research participant to refuse 
participation without coercion.  The CRA or PI will emphasize to all patients and parents in 
developmentally appropriate lay-language that being in the study is their choice, that they 
may choose not to participate or may change their mind at any time and it will not affect 
how their nurses or doctors care for them.
Since this is a minimal risk studies, consent will be obtained by one parent even if the 
other parent is alive, known, competent, reasonably available, and shares legal 
responsibility for the care and custody of the child.
We will re-approach and consent the children of participants if they turn 18 while they are 
still actively participating on study.  However, we request the waiver of consent for patients 
that turn 18 if no further data collection and study related activities are occurring, their data 
is limited to the continued use of existing data. 
29.6
Cognitively Impaired Adults
   
N/A
29.7
Adults Unable to Consent
     N/A
29.8
Consent for use of HUD
     N/A 
30.0
Process to Document Consent in Writing
Consent documents are attached in the appropriate section of the Click smart form, including 
identical REDCap consent forms for remote consenting. We are following the SOP as written. 
We will obtain written assent/consent from participants whenever possible, as a wet ink or 
signature. When this is not possible, we will obtain a digital signature to indicate willingness to 
participate.  Upon enrollment and randomization, the PI or Co-I’s will place a research note in 
the medical record to document the discussion and participants.  
As described in Section 29.0, we will also enlarge the print on consent forms and other study 
documents if we have an eligible patient who is visually impaired.
31.0
Drugs or Devices

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N/A
32.0
Good Clinical Practice
We are committed to conduct the described study per International Center for Harmonization of 
Good Clinical Practice (ICH-GCP).
33.0 
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Protocol Version Number: 17 
Protocol Version Date: 11/28/2023
Protocol Template (HRP-503)
Click Template Version: February  2016 
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