INSPIRE: A Multicenter Randomized Controlled Trial Integrating Health Informatics in a Scalable Stepped Care Self-Management Program for Survivors After Hematopoietic Cell Transplantation
Phase: PHASE3
Conditions: Hematopoietic and Lymphoid Cell Neoplasm
Sponsor: Fred Hutchinson Cancer Center

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FRED HUTCHINSON CANCER CENTER 
Barbara Ann Karmanos Cancer Institute 
Baylor University 
Center for International Blood and Marrow Transplant Research 
Cleveland Clinic 
H. Lee Moffitt Cancer Center
University of Kansas Medical Center 
Loyola University Medical Center 
Massachusetts General Hospital 
Medical College of Wisconsin 
National Marrow Donor Program  
Roswell Park Cancer Institute 
Sarah Cannon Cancer Institute 
Seattle Cancer Care Alliance 
University of Minnesota 
University of Pennsylvania 
Current version: 4/19/2022 
Previous version: 12/23/2021 
Title of Protocol: 
INSPIRE: A Multicenter Randomized Controlled Trial integrating health informatics in a scalable 
stepped care self-management program for survivors after hematopoietic cell transplantation 
Investigators List and Coordinating Center Staff: 
Investigator 
Professional Title 
Phone Number 
K. Scott Baker, MD
Principal Investigator 
Member, Director of Survivorship Program and Pediatric 
Blood and Marrow Transplant Program, Fred Hutch  
(206) 667-5594
 Karen Syrjala, PhD 
Sub Investigator  
Professor Emeritus, Fred Hutch and Professor of 
Psychiatry and Behavioral Sciences, UW  
(206) 949-4579
Navneet Majhail, MD 
Sub Investigator  
Sarah Cannon Cancer Institute 
(615) 534-4081
Jean Yi, PhD 
Senior Staff Scientist, Biobehavioral Sciences, Fred Hutch 
(206) 667-3435
Biostatistician: 
Wendy Leisenring, ScD 
Member, Clinical Statistics, Fred Hutch 
(206) 667-4374
Research Staff: 
Jenny Whitten, MPH 
Project Manager, Biobehavioral Sciences, Fred Hutch 
(206) 667-2162
Casey Walsh, PhD 
Senior Fellow, Biobehavioral Sciences, Fred Hutch 
(206) 667-3717
Coordinating Center: 
Fred Hutchinson CancerCenter 
Additional Performance Sites: 
Site 
Investigator 
Phone Number 
Cleveland Clinic 
Betty Hamilton, MD, Site PI, Associate Director, Blood and 
Marrow Transplant Program, Cleveland Clinic 
(216) 445-7580
Barbara Anne Karmanos Cancer 
Institute 
Joseph Uberti, MD, PhD, Site-PI, Professor and Director, 
Division of Hematology/Oncology, Wayne State University 
(313) 576-8760
Baylor University 
Jana Reynolds, MD, Site-PI, Physician, Blood & Marrow 
Transplant Services, Charles A. Sammons Cancer Center 
IRO REC'D 6/22/2022
FHCRC IRB Approval  
06 28 2022 
Document Released Date

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Center for International Blood and 
Marrow Transplant Research 
(CIBMTR)/Medical College of 
Wisconsin 
Bronwen Shaw, MD, PhD, Site-PI, Scientific Director, 
CIBMTR and Professor of Medicine, Medical College of 
Wisconsin 
(414) 805‐0700 
H. Lee Moffitt Cancer Center 
Heather Jim, PhD, Site PI, Assistant Professor, Health 
Outcomes and Behavior 
(813) 745-6369 
Loyola University Medical Center 
Patrick Stiff, MD, Site PI, Professor and Division Director 
of Hematology/Oncology, Co-Director, Oncology Research 
Institute, Cardinal Bernardin Cancer Center. 
(708) 216-8460 
University of Kansas Medical 
Center 
Joseph McGuirk, DO, Site PI, Professor of Medicine, 
Division Director, Medical Director, Blood and Marrow 
Transplant Program, Division of Hematologic Malignancies 
and Cellular Therapeutics 
(913) 588-9821 
Massachusetts General Hospital 
Areej El-Jawahri, MD, Site-PI, Assistant Professor of 
Medicine, Massachusetts General Hospital 
(617) 726-5765 
National Marrow Donor 
Program/Be the Match (NMDP) 
Jeffery Auletta, MD, Site PI, Chief Scientific Director, 
CIBMTR/NMDP/BTM 
(763) 406-4730 
Roswell Park Cancer Institute 
Theresa Hahn, PhD, Site PI, Professor of Oncology, 
Department of Medicine 
(877) 275-7724 
University of Minnesota 
Shernan Holtan, MD, Site-PI, Assistant Professor, Division 
of Hematology, Oncology and Transplantation 
(402) 559-6210 
University of Pennsylvania 
Alison Loren, MD, Site-PI, Assistant Professor of Medicine 
(215) 615-3138 
 
Emergency (24-hour) phone: (888) 344-5678. Fax: (206) 667-4356 
 
Supported by: 
National Cancer Institute grant R01 CA215134 

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TABLE OF CONTENTS 
 
 
STUDY SCHEMA 
 
1.0 
INTRODUCTION 
 
2.0 
BACKGROUND 
2.1 
Significance and Gaps This Project Will Fill 
2.2 
Preliminary Research 
2.3 
Self-Management Theory 
2.4 
Internet-Based Methodologies for Assessment and Intervention  
 
3.0 
OBJECTIVE 
 
3.1 
Primary Aims 
 
3.2 
Secondary Aims 
 
4.0 
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
4.2 
Exclusion Criteria 
 
5.0 
EVALUATION, INFORMED CONSENT OF SUBJECT, AND SECURITY 
 
5.1 
Internet Login Security 
 
6.0 
SUBJECT REGISTRATION 
 
7.0 
PLAN OF TREATMENT 
 
7.1 
Focus Groups 
 
7.2 
Selection for Treatment and Enrollment 
 
7.3 
Consent 
7.4 
Response to Elevated Depression Scores at Baseline or Later Assessments 
 
7.5 
Stratification and Randomization 
7.6 
Treatment 
 
8.0 
EVALUATION 
8.1 
Measures 
8.2 
Patient Reported Outcomes (PRO) 
8.3 
Process Measures 
8.4 
Cost and Resource Tracking 
8.5 
Medical Records 
8.5 
Internet Data Security 
 
9.0 
DRUGS, IRRADIATION AND MARROW/PBSC CELL ADMINISTRATION TOXICITIES AND 
COMPLICATIONS 
 
10.0 
GUIDELINES FOR ADVERSE EVENT REPORTING 
10.1 
Adverse Event Reporting/Institutional Policy 
10.2 
Study-Specific Adverse Event Capture and Data and Safety Monitoring Plan 
 
11.0 
DATA CONFIDENTIALITY 
 
12.0 
STATISTICAL CONSIDERATIONS AND DATA MANAGEMENT 
 
12.1 
Ethnic Categories 
12.2 
Design 
 
12.3 
Data Management  
 
12.4 
Endpoints  
12.5 
Primary Hypothesis 
12.6 
Secondary Hypotheses 
12.7 
Primary Endpoint Tests of the Specific Aim 
12.8 
Secondary Analyses 
12.9 
Process Descriptive Analyses 
 
13.0 
TERMINATION OF THE STUDY 
 
REFERENCES 

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STUDY SCHEMA: Phase III Multicenter Randomized Controlled Clinical Trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* 
TS/SCP = treatment summary and personalized survivorship care plan given to all intervention and control study participants. 
 
 
 
 
 
 
 
 
Eligibility identified through CIBMTR database and preliminary TS/SCP* prepared; Transplant 
center screens to confirm accuracy and approaches survivor for participation 
T1: Consent and complete baseline online with mailed or phone interview as backup after online consent; 
All who consent and complete baseline receive TS/SCP* 
Group 0: no impairment on primary endpoints 
Group 1: impaired on 1 or > primary or secondary 
endpoints: Distress/Depression or Health Care Adherence 
Intervention: INSPIRE mobile 
app, website and TS/SCP* 
with personalized content 
No impaired endpoints 
Any impaired endpoints 
T3: 3 months after T1 
T2: 6 - Week brief screen of outcomes in intervention, group 1 
participants 
Continue with online 
INSPIRE, TS/SCP 
Online INSPIRE, TS/SCP + 
Self-management calls 
T4, 12 months after T1 (8 months after T1) 
Randomized 
Randomized 
Control: TS/SCP* with control 
website, delayed access to 
personalized content 
Control: TS/SCP* with control 
website, delayed access to 
personalized content 

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1.0 INTRODUCTION 
 
This document is a Phase III clinical research protocol and the described study will be conducted in 
compliance with the IRB approved protocol, associated Federal regulations and all applicable IRB 
requirements. 
This study proposes that predictable health surveillance and unmet emotional needs of adult hematopoietic 
cell transplantation (HCT) survivors can be improved through a centralized, cost and resource-sparing, 
national program that optimizes health informatics and provides online expertise and stepped care 
telehealth assistance with using the program when necessary.  If successful, this project would provide 
long-term HCT survivors and their providers with a patient-centered program to facilitate managing their 
emotional and health care needs.  Long-term HCT survivors do not receive adequate care for their unique 
health and emotional needs due to lack of knowledge and resources to manage these needs in their home 
communities, although many of these needs have been well defined.  Lack of access to care increases 
premature morbidity and mortality in HCT survivors particularly for cardiovascular and metabolic disease 
(cardiometabolic) and subsequent malignancies. 
Among adult long-term cancer survivors, those who received HCT have a 9-fold increased risk of mortality 
related most commonly to cancer recurrence, subsequent malignancy s and cardiovascular diseases.[2-5]  
They are also at risk for poorer psychosocial health including cancer-related distress, with depression at 
higher levels than age-matched norms.[6-8]  By focusing on HCT survivors who are 2-5 years after 
treatment, we target a high risk group and build upon our previous experience delivering tailored online 
content with telehealth/phone based stepped care for those who do not improve at an interim assessment 
point at 6-weeks after randomization.   
The major goal of this protocol is to test the efficacy of the integrated, tailored online site, using a self-
management model of care that distributes survivorship care plans, tools and resources for management of 
distress and health care adherence directly to cancer survivors as the coordinators of their own health.  Our 
previous research has demonstrated efficacy in reducing depression and distress with survivors at a single 
site[9, 10], at six sites across the nation[11], and has tested the efficacy of providing a survivorship 
preventive care plan{4855}[10] With this protocol we will retain the focus on depression, distress and health 
behaviors, while improving the methodology by adding telehealth stepped care and leveraging the data 
registry and assessment infrastructure at the Center for International Blood and Marrow Transplant 
Research and the National Marrow Donor Program (CIBMTR/NMDP) for post-study sustainable 
implementation of the program. The protocol also builds on increasing recognition that a single online device 
or method will not meet the needs of all survivors.   
Although HCT is often considered distinct from other cancer treatments, the primary outcomes in the 
proposed research are also some of the most prevalent concerns and causes of mortality in other groups of 
survivors treated with standard therapy.[12, 13]  The methods we propose are relevant for any survivors 
who would benefit from cost and resource conserving interventions provided by online and telehealth 
modalities.  With these improvements and the extension of the intervention to twelve transplant centers we 
expect to strengthen both the reach and efficacy of the intervention tested in protocols 2258 and 2605, while 
we advance the science of delivering health behavior change models of care to cancer survivors. 
This protocol is a 12-site multicenter RCT (N=492), with Seattle as the prime site, partnering with transplant 
centers in Ohio, Minnesota, Wisconsin, Michigan, Massachusetts, Pennsylvania, New York, Florida, 
Kansas, Illinois, and Texas.  This provides age, region and rural/urban diversity.  Participants randomized to 
the intervention will receive immediate access to the tailored online program, with options for social-media, 
adding stepped care self-management calls for those not improving by a 6-week interim assessment for 
those in group 1.  Control participants will receive access to a website that provides annotated links to 
publicly available HCT and cancer websites as well as delayed internet site access.  Outcomes will be 
assessed at 6 weeks, 3 months and 12 months.   
 

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2.0 BACKGROUND 
Among adult long-term cancer survivors, those who received HCT live with some of the highest risks for life-
threatening chronic health conditions including cardiovascular disease, diabetes, osteoporosis, and 
recurrence or second cancers along with other risks.  Even more prevalent in HCT survivors are 
psychological symptoms that inhibit quality of life, specifically depression and cancer-related distress.  Many 
survivors have residual complications in specific domains with resultant impact on quality of life (QOL.)[14].  
Survivors have more difficulty after transplant if they struggle with chronic GVHD, have pulmonary disease, 
infection or other psychological or medical complications. [15-17] 
 
Significance and Gaps This Project Will Fill 
Despite their rapidly expanding numbers, survivors more than 5 years after HCT have been understudied 
both in defining their needs and in addressing long term complications through RCTs.  This protocol extends 
our knowledge of long term or late effects while testing treatment to reduce common problems that have not 
resolved on their own.  A major impediment to addressing needs of HCT survivors is their dispersion around 
the country, in areas lacking transplant-related expertise.  Online methodologies will allow us to enroll 
difficult to access survivors and will provide otherwise unavailable expertise and evidence-based guidelines 
for care.  With this internet, social-media and telehealth program, we optimize flexibility to respond at the 
readiness and at the time convenience of participants in a highly cost-effective modality since adding 
participants adds minimal cost.  We believe the program could improve standards of care and health 
outcomes for HCT survivors and address a major gap in care for these geographically dispersed survivors.  
Cancer-Related Emotional Distress and Depression.  Cancer-related distress is a significant problem for 
HCT and other with a negative impact on quality of life.[6, 18]   Distress is far more prevalent than clinical 
depression, with prevalence estimated at 43% in long-term HCT survivors and moderate to severe 
depressive symptoms in 13-15%.[7, 19-21]  Distress can be due to many factors such as uncertainty, 
cGVHD, managing the side effects of transplant, and financial stress.[22-24]  Our preliminary research 
found that 41% of 2-5 year HCT survivor study participants had elevated distress on the Cancer and 
Treatment Distress (CTXD) measure.[25]  In the cohort of 936 study participants, all but 1% of those with 
elevated depression scores also had elevated distress on the CTXD, suggesting that the CTXD captures a 
large proportion of depressive symptoms.[11]  Therefore, we believe our focus on CTXD distress as the 
primary outcome will also address depression needs for nearly all survivors, although we will still measure 
depressive symptoms as a secondary endpoint.  Risk factors for distress for allogeneic HCT include 
younger age, shorter time after HCT, and cGVHD.  For autologous HCT, comorbidities are a risk factor for 
distress.[26, 27]  Pre-HCT depression predicts later depression and other poorer outcomes[6, 27] as well as 
survival.[6, 28, 29]  We have demonstrated that the INSPIRE online program for HCT survivors can improve 
distress (see 2.2 Preliminary Research).  Others have demonstrated improved distress and post-traumatic 
stress in HCT survivors with telehealth cognitive behavioral treatment.[30] 
Cardiovascular Disease (CVD) and Metabolic Syndrome.  With a risk of premature CVD related death 
increased 2.3- 4.0-fold compared to the general population,[31, 32] HCT survivors are more likely to 
develop adverse CVD risk factors leading to development of metabolic syndrome (constellation of high 
triglyceride levels, low HDL-cholesterol, hypertension, high fasting glucose and increased waist 
circumference) which predisposes individuals to early CVD-related death.  Insulin resistance is the primary 
pathophysiologic mechanism and HCT survivors are more likely to develop hypertension, hyperlipidemia, 
and diabetes.[33-36]  In the Bone Marrow Transplant Survivor Study we examined diabetes, hypertension, 
and CVD events in 2+ year HCT survivors (n=1089) and found that allogeneic HCT survivors were 3.6 and 
2.0 times more likely to report diabetes and hypertension compared to siblings.  In addition, exposure to TBI 
increased the risk of diabetes 3.4 times.[37]  In a case-control study of 1379 HCT survivors compared to 
509 randomly selected individuals from the general population, the 10-year cumulative incidence of 
ischemic heart disease, cardiomyopathy, stroke, and all-cause death from CVD ranged from 3.5-6.0%.[38]  
Other mechanisms include cardiomyopathy and coronary artery damage due to chemotherapy and chest 
irradiation.[38-43]  Most cardiometabolic abnormalities can be screened for and treated.  Screening and 
preventative recommendations for CVD in HCT survivors have been recently published by a combined US 
and European task force.[44]  

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Subsequent Malignancy Risk.  As the leading cause of non-relapse late mortality, subsequent malignancy 
s after HCT are one of the most significant long-term health risks.  Numerous studies report the risk of a 
subsequent malignancy between 4 to 11-fold higher than in the general population.[45-51]  The types of 
subsequent malignancy s seen vary over time with earlier occurrence for myelodysplasia/acute myeloid 
leukemia and post-transplant lymphoproliferative disorders and longer latency for solid tumors.[52]  The 
cumulative incidence of subsequent malignancy s increases with longer length of follow-up, approaching 
8.8% at 20 years after HCT, and no evidence of a plateau.[49]  Risks of subsequent malignancy s after HCT 
are increased for skin, thyroid, oral cavity, esophagus, liver, breast, nervous system, bone and connective 
tissues,[46-48, 53] and risk factors include total body irradiation (TBI), young age at HCT, cGVHD and 
prolonged immunosuppression.[54]  HCT survivor specific guidelines have been published taking these into 
account,[54] and form the basis for the recommendations in the SCP that will be utilized for this study.[55-
58] 
Treatment Summary & Survivorship Care Plan (SCP).  SCPs are recommended for all cancer survivors, 
and should include the following information: (1) cancer type, treatments and their potential long term 
effects, (2) information about screening and preventive evaluations and their timing, and (3) 
recommendations about lifestyle practices.[59, 60]  When used in shared decision making as a cornerstone 
of self-management, SCPs may increase communication between oncologists and primary care 
providers.[61]  A majority of cancer programs face barriers to implementing delivery of SCPs (time and effort 
to create and disseminate) and thus are not providing them.[62-66]  Having a written plan may help 
survivors more than just talking with them about their SCPs.[67, 68]  Health informatics reduces  barriers to 
generating SCPs.[69, 70]  We are designing this protocol with dissemination in mind as has been 
recommended when using SCPs.[71]  To date, research testing delivery of a printed SCP, without follow-up 
to personalize the application of the information to the individual, has not found positive outcomes with 
regard to health care adherence (HCA) or distress, although survivors may report feeling positive about 
having received SCPs.[65, 72-84]  Personalizing an action plan for the individual through online interaction, 
and follow-up to address barriers by telehealth if needed, are necessary to make SCPs more effective.[85, 
86] 
 
Preliminary Research 
Preliminary Studies that Provide a Foundation for the Planned Methodology 
The scientific premise of the study builds on our preliminary research and work done in other chronic 
conditions such as diabetes that supports the value of online and telehealth self-management.  Online 
interventions for chronic diseases have proliferated, with mixed and at most modest success.[87-89]  Effect 
sizes are modest at best since those with greater problems are less likely to engage with the program.[90]  
Other than our INSPIRE study, only 2 interventions we are aware of with HCT populations have reduced 
distress and depressive symptoms; those required cognitive behavioral treatment delivered over the phone 
or in person.[30, 91]  Online programs are an attractive option for HCT survivors as many live far from their 
transplant center, and many go online for information.[92-95]  Social media provides access to other 
survivors through private groups and has been used in interventions with non-HCT cancer survivors with 
some success.[96-98]  A major limitation of online interventions is that many who sign up are already doing 
quite well in their health behaviors.[99, 100]  Literature search indicates few published RCTs of online 
interventions in cancer survivors, with mixed findings.[88, 101]  While a few interventions have been found 
to be efficacious,[102-108] the effect sizes are small and published studies tend to focus on feasibility and 
acceptability and not outcomes or efficacy.[69, 109-117]  Studies that provide options for participants to 
write content and complete action plans as part of the intervention have better outcomes than those where 
participants just read.[118]  This interactivity is an effective component of online interventions.[87, 119, 120]  
We propose to strengthen the proven online intervention from our INSPIRE multicenter RCT by creating a 
responsive design for use on all platforms, including social media, which will allow increased interactive 
options and improved personalization of the content.[121] 
PCORI-SCP Study 
This study had two phases; the first involved focus groups of HCT patients/caregivers and providers 
involved in survivorship care to get feedback on a SCP template and its implementation using the 

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centralized CIBMTR registry.  This qualitative research led to a final patient-centered SCP instrument that 
incorporated relevant clinical information from CIBMTR data and recommendations for screening and 
prevention of late effects based on specific exposures identified by the international long-term follow-up 
guidelines for HCT survivors (guideline effort led by Dr. Majhail).[122-124]  The final SCP is being tested in 
an ongoing RCT that compares usual care to the personalized SCP in HCT survivors 2-5 years post-
transplant.  Endpoints include patient survivorship confidence in knowledge, HCA, health behaviors, and 
HCT-related emotional distress at 6-months after the intervention.  As of June 2016, 464 of the planned 495 
HCT survivors have been enrolled through 17 transplant centers.  The PCORI-SCP study has laid the 
foundation and infrastructure for this project with CIBMTR/NMDP, the investigators and the SCP.  To 
strengthen the potential effect size of the SCP intervention, we will directly send the SCP to providers 
because studies have shown that reliance on survivors alone to disseminate a copy of their SCP to their 
provider is problematic.[69, 125]  Overall, interventions that give materials to both patients and providers 
have been more effective in general population studies that seek to improve overall adherence to 
recommended preventive care.[126, 127]  
INSPIRE Studies 
We have completed 2 INSPIRE RCTs (protocols 2258 and 2605), improving feasibility and implementation 
of the program while refining procedures for study administration across multiple sites, personalizing 
approach to survivors through informatics programming, and with a change in primary outcomes to focus on 
adherence. In our first INSPIRE study we administered the online program targeting primary outcomes of 
depression, distress and fatigue, without personalized content but with a 3-group randomization including a 
‘standard care’ control arm, the online intervention, and the online intervention plus a Problem Solving 
Treatment (PST) administered with 8 phone calls.[10, 128-130] Fred Hutch HCT survivors 3-18 years after 
HCT were eligible. Participation rate was 58% for those eligible and approached, with those age <40 years, 
non-white races, and >10 years after HCT less likely to enroll.[128] Once randomized to intervention, 77% 
logged in at least once and pages viewed did not differ by race, ethnicity, education, income, computer 
experience, donor type, healthcare adherence, distress or depression, but those likely to view 3+ pages of 
the site were more likely to be over 40 years and female. We found no efficacy for fatigue but did find 
important outcomes for distress and depression. For those who were impaired we found twice the rate of 
improved distress in those randomized to the intervention. Distress was more likely to improve in those age 
40+ and in those <10 years after HCT[10]. From these results, we designed the next multicenter INSPIRE 
study to address shortfalls. Given the incremental improvement relative to large resource requirements to 
administer the 8-session PST with masters or doctoral level trained clinicians, and lack of interest in the 
number of sessions by many participants, we did not retain PST in the next study. 
Our most recent multicenter INSPIRE RCT 
(CA160684) provides a platform and infrastructure for 
this study. The project approached N=2653 screened 
survivors 2-10 years after HCT at 6 national transplant 
centers, and enrolled 1064 survivors using the 
eligibility criteria as planned for this protocol. Of these, 
470 had impairments on one or more primary 
endpoints of depression, distress or overall HCA. Final 
12-month outcomes were completed in December 
2016, and analyses are in process.  In examining 
reach of the entirely online INSPIRE program with 
social media, participation did not differ by ethnicity, 
urban/rural residence, transplant intensity, or 
diagnosis, but was more likely for women, allogeneic 
HCT recipients, and age 40-60[11]. We conclude that 
strategies are needed to improve reach to men, 
younger and older adults. We designed this 
intervention to better target engagement and meet the 
personal needs of these subgroups. Preliminary 
analyses of 3-month outcomes indicate efficacy of the 
intervention for distress in those who access the online 
intervention. We see no interaction of intervention arm 
FIGURE 1. Survivorship self-management model 
(adapted from McCorkle and Colleagues, CA 
Cancer J Clin. 2011.)[1]. 

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outcome based on sex, age, race or time since HCT. However, viewing the online site interacts significantly 
with randomized intervention, indicating significantly higher rate of improvement for intervention recipients 
who engaged. 
Self-Management Theory 
Self-Management has been used to help patients cope with their chronic diseases (e.g., diabetes) and has 
been influencing cancer survivorship.[1, 90, 95, 131]  Foster and colleagues developed an online 
intervention to assist survivors in self-managing fatigue.[132]  Self-management has been used in cancer 
survivors to increase physical activity and improve diet,[133] and to reduce distress.[134]  In a meta-
analysis of online self-management studies, small to moderate effect sizes were found for anxiety, 
depression and quality of life.[89]  Younger survivors expect that at least some of their self-management will 
occur online.[135]  Self-management is a central premise of online interventions that attempt behavior 
change (see Figure 1.2 for our planned model of self-management).[136] 
Stepped Care Using Telehealth.  HCT survivors are amenable to using telehealth calls.[30, 137]  One 
stepped care intervention was found to be comparable to usual care, but the study was done in the pre-
transplant setting and enrolled patients with low distress.[138]  Telehealth has been as effective as face-to-
face interventions for cancer survivors.[139]  Our first INSPIRE program found that PST using 8 phone calls 
in addition to the online intervention, compared with the online program alone or delayed access control, 
was more effective than online alone for distress.[10]  However, we found great variety in the chosen targets 
for PST, such that it was difficult to measure outcomes, and many survivors did not feel a need for the 
extended telehealth calls.  For the stepped care methodology, we are using a self-management model we 
have tested with young adult cancer survivors, with 3 phone calls and content focused on achieving goals 
specific to the study endpoints of distress, cardiac and/or subsequent malignancy HCA, and retaining an 
emphasis on specifying personal goals and anticipating barriers and facilitators to reaching goals. 
This protocol tests an intervention to reduce common problems after HCT that have not resolved by two 
years after treatment, while extending our knowledge of risks for long-term or late effects in these survivors.  
It builds on prior online intervention research, with broad reach and high utilization. If efficacious in this 
multi-center RCT, it can be disseminated nationwide with limited maintenance costs.   
 
3.0 OBJECTIVE 
 
To determine the efficacy of a multicenter RCT of a self-management survivorship intervention that includes a 
personalized mobile application that is cross-device enabled, with internet and social media options, including 
stepped care telehealth, for adult 2-5 year HCT survivors enrolled from national transplant centers.  
Primary Aims  
1. Determine whether 2-5 year HCT survivors with elevated cancer-related distress or poor health care 
adherence, adherence to cardiometabolic or subsequent malignancy surveillance who are 
randomized to receive the online, patient-centered, self-management stepped care program will 
report reduced distress, and improved health care adherence for cardiometabolic or subsequent 
malignancy surveillance at 12 months when compared with an active control group who receive 
access to HCT survivorship best practices. 
2. Determine characteristics of intervention participants who require telehealth stepped care at 6-weeks 
because they 1) do not meet criteria for adequate knowledge of subsequent malignancy and 
cardiometabolic risks, or 2) do not report improved distress, or 3) have not logged in to the online 
program.  
3. Determine resources that would be needed to sustain the intervention as a national HCT 
survivorship program if implemented through the CIBMTR//NMDP. 
 
Secondary Aims 
 

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Secondary outcomes will include process measures of internet study reach and utilization, as well as 
depression, physical function, and knowledge of survivorship needs in HCT survivors.  
 
4.0 SUBJECT SELECTION 
 
Inclusion Criteria 
4.1a Received ≥1 autologous or allogeneic (related or unrelated) HCT with curative intent at a 
participating transplant center for a hematologic malignancy. 
4.1b Age 18 years of age or older at last transplant. 
4.1c Survival 2-5 years after last HCT when first approached for enrollment. 
4.1d In remission at time of study entry, may be receiving chemoprevention. 
4.1e Internet and email access. 
4.1f American and Canadian citizens, and/or those with mailing addresses in the US/Canada and/or 
temporarily residing anywhere outside the country (IE – military). 
 
Exclusion Criteria 
4.2a Development of invasive subsequent malignancy after HCT other than non-melanoma skin 
cancer, in the past two years. 
4.2b Medical or other issue prohibiting computer use, reading or ability to comply with all study 
procedures or unable to communicate via phone (e.g., significant vision, hearing or cognitive 
impairment, major illness, hospitalization). 
4.2d Residing in an institution or other living situation where health care decisions are not made by 
the participant (e.g., hospitalized, prisoners, living in a rehabilitation facility). 
4.2e Does not complete baseline PRO assessment items required to determine stratification or 
whether the survivor meets inclusion and exclusion criteria. 
4.2f Non-proficient in English (written and spoken). 
 
5.0 EVALUATION, INFORMED CONSENT OF SUBJECT, AND SECURITY 
 
After consortium transplant centers have gone through their individual processes to confirm participant 
eligibility to participate in INSPIRE and participant contact information, the sites will approach survivors 
treated at their facility with two letters, sent approximately two weeks apart with three phone calls in 
between, that include study information and a request for consent to communicate the survivors’ contact 
information to NMDP and to the Coordinating Center at the Fred Hutch.  Survivors can indicate interest in 
the study by returning a signed response form attached to the consent letter indicating that they permit their 
contact information to be sent to NMDP/Fred Hutch, or by calling their transplant center Study Coordinator, 
calling the study toll-free phone line directly, emailing the study-specific address (inspire@fredhutch.org), or 
going directly to the study URL (inspire4survivorship.org), entering their unique temporary study ID listed on 
their letter and signing up directly on the secure study internet site registration page where they can 
consent, provide registration information and setup their account.  If survivors provide permission for 
NMDP/Fred Hutch study staff to contact them by signing and returning their mailed response form to the 
consortium sites, by calling study offices, or by giving verbal permission for study contact over the phone to 
the consortium sites, NDMP will contact the survivors and discuss protocol consent details with them.   
 
Participants who express interest in the study after a phone call or email communication with NMDP will be 
sent an email with a link to the study secure URL.  There they can enter their unique study ID, which will link 

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them into the secure site where they can register. Participants will have a choice to register with either an 
email and password of their choosing, or by using their login information associated with their Facebook or 
Amazon account. Once registration is complete, participants can sign the consent form.  The consent, which 
includes HIPAA content, will be electronically signed online within the secure study registration site.  
Survivors will be able to review and print the consent document before signing or downloading a pdf of the 
consent.  A blank version of the consent is also accessible at all times on the website.  If survivors have 
questions or concerns before signing the consent, we encourage them to contact the study at the toll-free 
phone line or by email to the study address.  Consent will be obtained using forms approved by the 
Institutional Review Board of the Fred Hutch, and the Coordinating Center will establish IRB Authorization 
Agreements with each of the consortium centers.  Potential participants at these centers will not be 
contacted for enrollment eligibility until the center has IRB Authorization Agreements in place.  All 
substantive modifications to the consent will follow the same procedure of securing IRB approval at the 
Coordinating Center. 
If survivors have indicated interest but have not registered or logged in to register, NMDP Study 
Coordinators will contact survivors with reminder emails and phone calls for six weeks to find out whether 
any issues can be addressed to facilitate registration.   
Survivors may submit emailed questions, comments or requests at any time to study staff.  They also may 
call the toll-free study phone line and their call will be returned within 2 business days. 
 
Internet Login Security 
The internet site entry page after randomization will require the participant to login, with either an 
email and password of their choosing, or by using their login information associated with their 
Facebook or Amazon account. After initial study login, participants will have the option to place a 
cookie on their computer for the internet program future access without a password, but full login 
security will be in place during online assessment phases of the study. Once a patient is signed 
into the INSPIRE application, they will go directly to their survey during the survey window until 
the survey has been completed. We have used the process for a patient to create their own user 
name and password similarly in two previous INSPIRE RCT studies with internet security review 
and approval at the six previous study sites and with no problems detected. 
 
6.0 SUBJECT REGISTRATION 
 
Subjects will be assigned to the protocol by the Fred Hutch Study Coordinator, who will register the patient 
with the Fred Hutch Data Management Office (206-667-4728).  Since consent occurs only through the study 
website, which is managed by the Coordinating Center, the participating consortium centers will not be 
involved in subject registration.  After the eligible subjects have been registered, subjects will be randomized 
by the Fred Hutch Data Management Office (DMO), Monday through Friday between 8:30 and 4pm 
PST/PDT.  The DMO will email the randomization assignment back to the Project Manager at the 
Coordinating Center.  The DMO can be paged, if necessary, at 206-995-7437.  The Project Manager will 
receive the randomization assignment. She will input the randomization arm into the databases to trigger 
the programmed website access (intervention or control) for the participant, and will email participants their 
link to the study site. 
 
7.0 PLAN OF TREATMENT 
 
Intervention Selection and Approach 
The CIBMTR data registry contains 3765 potentially eligible 2-5 year survivors including 14% minorities 
from the 13 participating centers. The study Biostatistician will develop a Statistical Analysis Software (SAS) 
program for random selection of potentially eligible participants with oversampling of minorities (initially all 
eligible minority cases will be approached) until a minimum of 15% of those randomized are minority race or 

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ethnicity. The remaining non-minority survivors will be randomly ordered. Each participating center will be 
sent their randomized approach lists in blocks of 25 cases. Based on our previous INSPIRE enrollment 
experience with similar eligibility, we found that 26% of cases were not eligible after further screening. We 
project that we will enroll and randomize 51% of eligible non-minority survivors and 40% of minority 
survivors. Thus we expect we will approach approximately 1358 (36%) of potentially eligible cases, with 
26% not eligible after approach, to achieve our total projected enrollment N=492 to the randomized study.   
First contact will be made with a letter of approach from the site PI and Study Coordinator.  The letters of 
approach from the consortium sites will request permission to provide contact information to NMDP as the 
follow-up coordinators and to Fred Hutch as the Coordinating Center.  Survivors who have opted out of 
contact or are lost to follow-up will not be approached either by the Coordinating Center or consortium sites.  
In the order designated by the program from the study biostatistician until enrollment goals are met, 
potentially eligible survivors will be sent a letter of approach from their transplant center describing the 
study, and requesting permission to provide their contact information to NMDP/Fred Hutch.  The letter will 
include a response form, stamped return envelope, study email address, internet URL for the study, 
temporary participant study ID code and toll-free phone number for survivors to contact NMDP/Fred Hutch 
to discuss the study or to contact the transplant center Study Coordinator or PI.  NMDP will be the default 
contact for survivors through the study toll-free line, but contacts may be escalated to Fred Hutch as needed 
based on survivors’ questions or concerns about study participation.  Initial letter contact will be followed 
with three phone calls and then one more letter to those who do not respond with a total of up to six phone 
calls until the participant is reached and indicates interest or declines to participate.  Up to three voice 
messages will be left.  After participants return the response form to the consortium sites agreeing that their 
contact information can be given to NMDP/Fred Hutch study staff, or participants log onto the study internet 
site and consent, or they contact the Study Coordinators directly by phone or email, all further study 
activities will be handled by the NMDP and the Coordinating Center.  The exception is if survivors from the 
consortium sites have medical questions.  As agreed by the consortium PIs, such questions will be directed 
by a study investigator at Fred Hutch to the PI at the participant’s transplant center.   
Enrollment will continue until targeted goals are met, as defined for each targeted outcome in Table 3.  We 
expect this to require 492 participants enrolled in the randomized study. 
Consent  
Before accessing the study questionnaires or any of the secure internet content, the electronic consent form 
must be agreed to and submitted.  Consent will be indicated to include: 1) communication by email and 
phone (required), access to the secured online internet site (required), and social media (optional), 2) 
response to self-report assessments, and 3) allowing study access to medical records.  After consenting, 
survivors will be registered for the study with the Fred Hutch study registration office.   
Consent, with HIPAA content, will be electronically signed online.  Survivors will be able to review and print 
the consent document before consenting via the online site, as they desire.  If survivors have questions or 
concerns before signing the consent, we encourage them to contact us by phone or by email 
(inspire@fredhutch.org). Consent will be obtained using forms approved by the Institutional Review Board of 
Fred Hutch. 
Consenting Information about Treatment Conditions.  Survivors will be told that the research focus is on 
decreasing distress and increasing health care understanding and actions for people 2 to 5 years after 
transplant.  They will be told that there are two possible groups: 1) full INSPIRE online program and study 
materials access, with mailed treatment summary and survivorship care plan (TS-SCP) for the survivor and, 
if they choose to provide names, for their health care providers, with an optional orientation call at 2 weeks 
and optional self-management calls at 6 weeks; or 2) access to a study website with links to other online 
resources for survivors, with delayed INSPIRE program access after completion of the 12-month 
assessment.  They will be advised that they will be contacted if we detect severe emotional needs during 
the course of the study. 
The first 100 participants who are approached, with an expected N=20 enrolled for the randomized study, 
will be treated as “run in” participants to test the website programming and study intervention procedures. 

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They will be approached and treated as regular participants from survey to data management randomization 
and intervention. These participants will receive the same access and study experience as later participants, 
but they will not be included in the outcome analyses or the N=492 sample size.  Thus the total enrollment is 
projected to be N=512. 
Response to Elevated Depression Scores at Baseline or Later Assessments 
After baseline assessment, responses on the primary outcomes will be scored to determine whether the 
participant meets eligibility criteria for randomization and whether a suicide and depression screening 
trained study investigator needs to contact the participant for concerns about major depression.  At least 
weekly, the Project Manager will review baseline assessments.  She will bring any severe depression or 
other concerns to the attention of Drs. Yi, Syrjala, Baker or Majhail.  Of note, the depression measure, PHQ-
8, does not include a question about suicidal thoughts. 
If possible major depression or risk to the survivors’ health in other ways is detected, we have planned 
standard, IRB approved procedures   With a score of 20 or greater reported on the PHQ-8 depression 
measure, a study investigator trained in depression and suicide screening will attempt to contact the 
survivor to by phone to screen for suicide risk, and encourage them to discuss their symptoms with their 
home medical provider.  The study investigator will leave 3 phone messages over 2 weeks with a phone 
number to contact the study investigator. The study investigator may also send an email message, without 
PHI or indication of the reason for the call.  All email or voice mail will indicate only that the study 
investigator is contacting the participant about his/her participation in the study, and will ask the participant 
to contact the study investigator.  If there is no contact with or response from the participant after 3 attempts 
over 2 weeks, the study investigator will mail a letter to the participant stating that the study team is 
attempting to contact the participant, and providing the study toll-free phone number and email address, 
after which no further attempts to reach the person will be made.  Once a participant is reached, the study 
investigator `will complete the safety evaluation which will include: 1) the nature of the suicidal thoughts or 
severe depression, 2) any suicide plan, 3) risk factors for suicide, 4) family, close friends or health care 
providers who are aware of or treating the participant’s depression and/or suicidal thoughts or plans, and 5) 
overall risk for suicide and safety of the participant.  If safety concerns remain, the study investigator may 
contact 911 or a family member to take the participant to an emergency room for evaluation, or follow other 
requirements indicated by state law (e.g., calling the county designated mental health professional 
[CDMHP] to evaluate the participant for potential involuntary psychiatric hospitalization).  If safety is not 
judged to be an immediate risk, the study investigator and participant will review available local resources 
and make a plan for addressing severe depression or suicidal thoughts.  The study investigator will 
encourage the participant to discuss thoughts and symptoms with his/her health care provider as 
appropriate.  If needed, the study investigator may follow-up with an additional call to assure participant 
safety and use of available resources.  A call record, with written risk assessment information, will be stored 
in a locked file separate from other study data.  The form used for this depression and suicide screening is 
in the attachments.  The study investigator will inform a study PI about the safety evaluation within 72 hours 
after ensuring the safety of the participant.  The PI will decide if an adverse event has occurred.  This 
contact will also occur if any participant receives a score of 20 or greater on the depression measure 
(indicating severe depression) at 3 or 12 month outcomes.  These survivors will remain eligible for study 
randomization.  In our previous internet studies, <1% indicated severe depression requiring a phone call. 
Stratification and Randomization  
Those who complete the baseline assessment but are determined to be ineligible after baseline assessment 
will be given access to the online INSPIRE site as a courtesy.  Those who meet all eligibility criteria will be 
randomized based on the stratification criteria described below.  If any one of the following scores on 
baseline patient reported outcomes (PRO) is impaired, the participant will be randomized within ‘Group 1,’ if 
no scores are impaired the participant will be randomized within ‘Group 0’ for the primary and secondary 
endpoints: a) Cancer and Treatment Distress (CTXD score <0.9 vs. ≥0.9), b) cardiometabolic health care 
adherence (<80% vs.≥80%) and c) cancer health care adherence (<80% vs.≥80%).  Note that each of these 
endpoints of the study has a measure cut-point for eligibility for Group 1 randomization required at baseline, 
and these are the threestratification parameters below.  However, all eligible participants will be randomized 

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as they will all contribute data for secondary analyses.  After minimum required baseline assessment is 
complete and eligibility confirmed, the Project Manager will fax the registration office with stratification data 
for randomization.  Stratification factors are based on whether the participant exceeded or fell below the cut-
offs for these endpoints, as determined by baseline screening values, prior to randomization.  We will not 
stratify on age, sex, cGVHD treatment, or race/ethnicity because we believe these will be balanced 
adequately between study arms through random selection, and we will adjust, or stratify on these factors as 
needed in analyses.  Participants in both groups will then be randomly assigned to either the “Control” or 
“Intervention” arms.  The PIs and Biostatistician will review participation rates within each stratum annually 
and adjust the algorithm if needed.  Once enrollment is complete, the sampling probability relevant to each 
participant will be stored in the database for use in analyses.  Randomization assignment of the participant 
will be communicated to the participant through email.  A diagram of study randomization is shown in Figure 
2 and will occur as follows. 
Group 1. Meets all eligiblity and has one or more elevated distress or low cardiometabolic or cancer health 
care adherence and is randomized to one of the two groups, intervention or control. 
Group 0. Meets all eligiblity and does not have elevated elevated distress or low cardiometabolic or cancer  
health care adherence and is randomized to one of the two groups as in Group 1. 
Group Y. Does not meet eligibility criteria (in active cancer treatment in the past 2 years, transplanted for 
disease other than hematologic malignancy or myelodysplasia, more than 5 years after first or last 
transplant.) Not randomized, but if consents and completes assessments (which determine final eligibility 
criteria) is given access to the INSPIRE online program but does not receive mailed TS-SCP, phone calls, 
or the follow-up assessments at 1, 3, and 12 months.  .  
Group X. Not randomized; consented but did not complete baseline assessment; is not given access to the 
INSPIRE online program but still registered with Data Management.  
 
 
Figure 2. Diagram of randomization and treatment intervention possibilities. 
 
 
T1: Baseline assessment  
Completed and scored 
Group 1 
Scores indicate 
problems 
Group Y: 
Ineligible 
Group 0 
Scores indicate 
no problems 
Group X 
Did not complete 
assessment 
T2: outcome assessment at 6 weeks (-1 week to +4 weeks) 
T3: outcome assessment at 3 months (-2 weeks to +4 weeks)  
T4: outcome assessment at 12 months (-4 weeks to +12 weeks) 
Data management randomizes 
study participants 
Control 
Delayed program access 
Intervention 
Full program access 
No program 
access 
Program access, 
no randomization 

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Blinding 
To reduce potential for contamination of the treatment and control conditions, the site investigators and 
NMDP study coordinators who contact survivors to respond to study questions or for incomplete 
assessments will be blinded to randomization.  Information on randomization will be kept separate from the 
other data in a protected file viewable only to investigators and study staff who have intervention contacts 
with participants. 
Participant Randomization Notification 
To maintain randomization blinding of NDMP study coordinators completing the study assessment contacts 
with participants and study status tracking, the Project Manager will email survivors their randomization with 
internet site link and contact reminders for questions.  She will give all participants the options to call the 
study toll-free line or the Coordinating Center with any questions.   
Treatment 
Intervention: Full Internet Program Access  
Treatment Internet Site and Related Materials.  The INSPIRE internet site will be continuously 
available to the participant for the study year.  It will consist of the following six levels:  1) A greeting 
home page, with links to each target area.  2) Lift Mood, emphasizing managing stress and 
emotions.  3) Boost Heart Health pages focusing on implementation of the SCP addressing overall 
health behavior recommendations with a focus on cardiometabolic health.  4) Prevent Cancer pages 
focusing on implementation of the SCP for cancer screening tests and behaviors that prevent 
cancer.  5) Getting Connected, focusing on social activation and using resources to improve mood.  
6) Tips and Tools, with downloadable content and tracking worksheets for monitoring progress on 
goals. There will also be options for participants to send secure messages with questions or 
comments on any topic to the study and links to the study Facebook page maintained and monitored 
by the study staff.  The secure Facebook page will offer notices and encourage return to the site.  
Twitter and Instagram will have the same messages.  We will increase motivation by email ‘pushes’, 
and mobile application notifications to cue survivors to links that match needs, and encourage use 
and tracking of the SCP.  After completing the 12-month assessment, participants will receive a $25 
gift card from Amazon, to be mailed to them as study payment. 
Tailoring will include: 1) use of the participant’s first name on logins, 2) recommended links to site 
landing pages specific to the participants’ baseline elevated scores, 3) participants will receive 
tailored ‘push’ email links at 8 times after randomization, and 4) participants will receive mailed 
individualized TS-SCP with information about their cancer treatment and current recommended 
preventative health care guidelines.  Health care providers listed on the baseline assessment will be 
sent as TS-SCP with an abbreviated listing of the recommended SCP screening and a focus on 
cardiometabolic health and cancer screening.   
Stepped Care Self-Management Telehealth Contacts.  Group 1 intervention participants who at the 
T2 (6 weeks) indicate no use of the online program, or lack knowledge of their cardiometabolic or 
subsequent malignancy risks, or do not indicate improvement in distress, will receive telehealth 
contacts.  These will be three to four calls via phone.  Calls will last 20-30 minutes for the first call 
and 10-20 minutes for the ‘booster’ calls.  They will be led by a ‘coach’ trained by the clinical 
investigators in HCT and self-management skills, using a manual to deliver call content focused on 
assisting survivors with using the self-management skills in the online program.  This is a brief, 
manualized intervention is designed to be sustainable without extensive clinical training and has 
been tested.  The first session will focus on impairments indicated by the T2 6-week screening PRO.  
The coach and participant will make shared decisions, led by the participant, on goals and an action 
plan for addressing deficits, and elicit potential barriers and their solutions based on chronic disease 
self-management models (Figure 1).[1, 84, 133, 140-143]  The second and third ‘booster’ calls will 
review progress on the action plan, address barriers and agree on a revised plan if needed.  
Participants and coaches will decide whether a fourth call would be helpful based on the complexity 
and difficulty of the goals and action plans.  The contacts will be audiotaped for process evaluation 

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of content and fidelity to the self-management script.  
Control: Website with Links and Delayed Internet Program Access 
Participants randomized to receive the website providing links to existing transplant and cancer 
survivor sites and delayed access to the INSPIRE internet program (control) arm will be notified that 
they will be able to access the secured internet content after one year, and in the meantime will be 
provided with links to existing online resources and survivor sites.  They can access the study 
content after they have completed their 12-month outcome assessments.  At that time, the Project 
Manager will have their web permissions modified so that all internet study content can be accessed 
until the study closes.  Internet site access will be as described above in 7.5.1. Control participants 
will also receive mailed individualized TS-SCP at randomization. After completing the 12-month 
assessment, control participants will also receive a $25 gift card from Amazon, to be mailed to them 
as study payment. 
Group Y Website Access  
Survivors who do not meet inclusion criteria will be ineligible for randomization.  These survivors will, 
however, have full access to the internet site if they have completed the required baseline 
assessment.  But they will not receive the mailed TS-SCP or the follow-up assessments at 1, 3, and 
12 months. 
Group X 
Survivors who have consented to participate but not completed the baseline assessment cannot be 
randomized and cannot access the study internet content at any point. 
  
8.0 EVALUATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1.   PRO Measures and schedule of administration (T2 for intervention-only participants 
described in section 8.1) 
8.1 Patient Reported Outcome Measures 
T1 
Baseline 
Screening 
T3 
3 month 
Outcome 
T4  
12 month 
Outcome 
Primary Outcomes 
Cancer and Treatment Distress (CTXD) 
X 
X 
X 
Health Care Adherence (HCA)   
X 
 
X 
Secondary Outcomes 
Patient Health Questionnaire-8 Depression 
(PHQ8)  
X 
X 
X 
Moderators and Risk Factors 
Computer and Mobile Phone Use 
X 
 
 
Background: potential barriers to PCA  
(age, income, rural/urban, gender, cancer and 
treatment history, current medical history, 
medications)  
X 
 
 
GVHD Symptom Scale (allogeneic only) 
X 
 
 
Medical Comorbidities and Medications  
X 
 
X 
Mediators 
Knowledge of Survivorship Needs 
X 
X 
X 
Health Self-Efficacy  
X 
X 
X 
Study Evaluation 
Evaluation of Program and Participation 
 
 
X 
ESTIMATED TIME REQUIRED  
30-40 
10-15 
25-35 

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Measurement Selection Rationale 
Study measures have all proven sensitive and specific in our research with HCT survivors, except 
Knowledge of Survivorship Needs which is in testing.  Most are standardized measures with population 
norms.  Measures were selected to target outcomes or as descriptive variables or mediators or moderators 
of outcomes as defined by the aims. 
 
Measurement Time Points 
The measures and their administration time points for three of the four assessments are listed in Table 1: 
baseline, 3 and 12 months. For group 1 intervention participants only, there will also be a brief orientation 
call for the study at 2 weeks, and an assessment at 6 weeks, that determines distress and knowledge of 
survivor health risks. Distress is measured on a 0-10 distress thermometer rating scale (0=no distress, 
10=extreme distress) is >5, along with the first 2 items on the PHQ scored <=2 indicating low distress and 
depression symptoms. The distress thermometer is a widely used, validated and reliable measure of 
distress in cancer survivors.[144-147]  Knowledge of HCT Survivor Health Risks is an 11-item screening for 
cardiometabolic and subsequent malignancy  risks. Items are scored 0 (‘my risk is higher’) or 1 (‘my risk is 
not different’ or ‘not sure’) with a score >2 indicating inadequate knowledge of risks and eligibility for 
telehealth stepped care. The third criterion is whether the participant has viewed at least 3 pages of the 
online INSPIRE site.  If any one of these 3 progress criteria are not met, intervention participants are 
stepped into telehealth self-management contact as described in Treatment section 7.5.1. 
 
Baseline and Outcome Assessments  
After consent, survivors will be directed to the 30-40 minute online baseline assessment.  Measures are 
listed in Table 1.  They will have the option to return to the assessment, if it has not been completed.  This 
process will be repeated at 3 and 12-month outcome assessments.  If the assessment is not completed, the 
NMDP study coordinators will contact the participant by phone and determine whether the assessment can 
be completed on the internet, if not, whether the assessment can be completed by mail. 
 
 
Patient Reported Outcomes (PRO)  
Primary Outcomes  
Cancer and Treatment Distress (CTXD).  The CTXD is a 22-item inventory of distress or worry 
related to stressful events for cancer survivors.[25]  The measure was developed by the PI from 
structured interviews with HCT patients, nurses and physicians and has been tested with long-term 
survivors (N=1978).  Testing supports its value as a predictor of health outcomes and it has been 
used in several RCTs.[6, 148-150]  Internal reliability for HCT survivors is α = .93. There are 6 
reliable subscales: uncertainty, health burden, family strain, finances, medical demands, 
identity.[151] 
 
Health Care Adherence (HCA).  The HCA is derived from the Cornell Service Index.[152]  We have 
tested the format with several thousand HCT survivors.[153]  Scores are transformed to proportion 
of HCA recommendations met.  For a primary outcome, we use HCA items reflecting adherence to 
cardiometabolic surveillance (HCA-cardio; 5 items).   Additional items measure adherence to 
subsequent malignancy surveillance (HCA-cancer; 7 items) and will be a secondary endpoint (see 
below).  Items are adjusted for sex and age at which tests are recommended.  An item is scored as 
‘adhered to’ if the participant is under the age of recommended test onset.  Cut point for determining 
adherence for each item is based on the frequency of testing recommended in guidelines (annual, 
every 3 or 5 years).  Score is calculated as percentage of tests completed.  Since adherence is 
important to reduce mortality risk, we set the cutoff for not meeting adherence criteria at <80%.  In 
our previous 6-site INSPIRE study, we found 34% not adherent to HCA-cardio surveillance using the 
above criteria.  Validity for HCA-cardio is supported by the following associations (p<.01 for all): 

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HCA-cardio was higher in those with self-reported high blood pressure, diabetes, history of heart 
attack, and those told they had cardiomyopathy or atherosclerosis.  Discriminant validity is supported 
by no significant association of HCA-cardio with report of a history of second cancers, osteoporosis, 
or thyroid problems.  The 21 Barriers to HCA items were defined from qualitative patient reports of 
HCT survivors.[154]  With 6 subscales, the overall and subscale reliabilities are all α > 0.80.  Mean 
score with cut point >0.45 will be used as an Aim 2 predictor. with subscales: Cost, Avoidance, Time, 
Knowledge, Provider Access, . 
 
 
Secondary Outcomes  
Patient Health Questionnaire (PHQ-8).  The 8 item PHQ8 scale is highly reliable, valid and widely 
utilized in medical and psychiatric studies.[155-157]  We have extensive data documenting reliability 
and utility in survivors. 
 
Health Care Adherence for subsequent malignancies. As described above, our assessment of HCA 
includes 7 items measuring adherence to surveillance for subsequent malignancies.  Scoring will be 
carried out as described for the primary HCA-cardio outcome and will use a cutoff for not meeting 
adherence criteria at <80%. In our previous 6-site INSPIRE study, we found 45% not adherent to 
HCA-cancer surveillance using the above criteria.  Validity for HCA-cancer is supported by a 
marginal association with history of second cancer, with a 17% cumulative incidence rate in study 
participants (62% adherent vs. 54% occurrence rate for second cancers in the early post-HCT 
period; p =.074).   
 
 
Moderators for Primary Outcomes and Risk Factors for Secondary Analyses  
Background.  Standard questions will define demographic characteristics including age, income, 
rural/urban by zip code, gender, ethnicity, education, work status, current medications, and cancer 
history. 
Comorbidity Index and General Health.  The self-report comorbidity index has strong kappa 
agreement with the Charlson comorbidity index, which is scored from medical records.  Studies 
document the accuracy of HCT survivor self-report of medical diseases and problems when 
compared with medical records.[165][166]  Medications will also be reported.  It has documented 
validity and test-retest reliability, and used in our previous studies.[165-167] 
GVHD Symptom Scale.  For allogeneic HCT recipients, a reliable, validated measure based on 
cGVHD severity; type and duration of medications for cGVHD.[168]  
 
 
Mediators for Primary Outcomes 
Knowledge of Health Care Needs.  This 15-item measure addresses 2 factors: 1) knowledge of 
treatment and related risks, including cardiometabolic and second cancer risks, and 2) 
understanding of health care recommendations and emotional health resources after HCT as 
included in our intervention.  With N=936 participants in our previous INSPIRE study, alpha is strong 
for the overall score (α = .92) and factors (α = .82, (α = .93).  The measure is derived from a similar 
measure developed in our SCOEN collaborations.[82] 
Health Related Self-Efficacy.  This measure reflects beliefs about health-related self-efficacy.[169, 
170]  In testing with N=860 HCT survivors, the measure has reliability of α = 0.86. 
 
Process measures   
These measures will provide intervention engagement, fidelity, and descriptive data.  After intent to treat 
analyses, they will provide covariates for analyzing differential efficacy of the intervention.  

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Reach: rates of participants approached vs. registering, by age, urban/rural, ethnicity, and race diversity 
criteria.  Engagement based on: Adoption: rates of visit to the site at least once and view at least 3 pages.  
Pages Viewed: number of logins and pages viewed per participant, and which pages viewed within content 
areas.  Modalities Used: rates and characteristics of those using the internet site, social media, and 
requiring telehealth contact.  Attrition: rates of request to withdraw or non-response to requests to complete 
assessments.  Support Requests: rates and types of calls, emails, and comments (technical help vs. 
content of website questions or comments).  Study Evaluation.  Participants will report on use of the SCP, 
whether they took it to their providers and/or discussed it, use of the internet site, satisfaction, helpfulness 
and suggestions.  Telehealth Contacts Fidelity, Engagement, and Extent participant completed action plan, 
and audiotape fidelity ratings by Dr. Baker and Yi for a minimum of 20% of sessions per coach 
interventionist. 
 
Cost and Resource Tracking 
We will track the costs of maintaining the program if disseminated (not including elements required for 
research implementation) as indicated by 1) materials, 2) programming for site maintenance, technical 
problem solving, and updating content and maintaining social networking, 3) multi-center staff time for 
identifying, approaching and tracking participants, and responding to participant comments 4) coordinating 
center and CIBMTR/NMDP staff time for tracking participants, responding to participant comments and 
requests, and responding to technical problems.  We will track costs separately for the self-management 
call component.  Site staff will report cost summaries quarterly.  These will be standardized to report the 
cost per participant who reaches at least one of the primary endpoints for the study, specified for each type 
of cost (materials, staff time) as well as total costs.  Because we will track the costs of preparing SCPs and 
internet links provided to the control group and will know their outcomes, we will also be able to calculate an 
incremental cost-effectiveness ratio for the internet intervention program compared to the control cost-
effectiveness, similar to the method described by Mandelblatt and colleagues.[171, 172] 
 
Medical Records 
For cohort description and covariates, diagnoses and treatment-related variables will be downloaded or 
abstracted from the participating transplant center medical records. 
 
Internet data security  
The study internet site from the previous INSPIRE research project underwent review with and met 
specifications from the Information Security Office at Fred Hutch in July 2019.  Fred Hutch developed a 
secured patient portal, to secure the identities of participants and their data.  To protect the privacy of 
patient data, once participants ‘submit’ their assessment responses or two weeks go by without activity, 
assessments completed are permanently secured behind a firewall and cannot be accessed again. The 
same site and portal will be used in the current project, with updated content. 
 
9.0 DRUGS, IRRADIATION AND MARROW/STEM CELL ADMINISTRATION TOXICITIES AND 
COMPLICATIONS 
 
Not applicable. 
 
10.0 GUIDELINES FOR ADVERSE EVENT REPORTING 
 
Adverse Event Reporting/Institutional Policy 
 
The following guidelines are the minimum Cancer Consortium IRB adverse event (AE) reporting guidelines. 
Protocol-specific additional reporting requirements for adverse events are addressed in Section 10.2.  In 

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accordance with institutional policy, all adverse events which in the opinion of the principal investigator are 
unexpected and related or possibly related to the research and serious or suggest that the research places 
research participants or others at greater risk of physical or psychological harm than was previously known 
or recognized be reported to the IRB within 10 calendar days of learning of the problem. 
Institutional support of trial monitoring will be in accordance with the Fred Hutch/University of Washington 
Cancer Consortium Institutional Data and Safety Monitoring Plan.  Under the provisions of this plan, Fred 
Hutch Clinical Research Support coordinates data and compliance monitoring conducted by consultants, 
contract research organizations, or Fred Hutch employees unaffiliated with the conduct of the study.  
Independent monitoring visits occur at specified intervals determined by the assessed risk level of the study 
and the findings of previous visits per the institutional DSMP. Independent monitoring meetings occur 
annually or more often as determined by the findings of the previous meetings (see DSMB charter.) 
 
 
Definitions: 
Adverse Event - Any untoward medical occurrence in a patient or clinical investigation subject administered 
a pharmaceutical product, medical treatment or procedure and which does not necessarily have to have a 
causal relationship with this treatment.  An adverse event can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal product, medical treatment or procedure whether or not considered related to the 
medicinal product.  
 
Life-threatening Adverse Event – Any adverse event that places the patient or subject, in view of the 
investigator, at immediate risk of death from the reaction.  
 
Unexpected Adverse Event – An adverse event is “unexpected” when its nature (specificity), severity, or 
frequency are not consistent with (a) the known or foreseeable risk of adverse events associated with the 
research procedures described in the Protocol-related documents, such as the IRB-approved research 
protocol, informed consent document and other relevant sources of information such as product labeling 
and package inserts; and are also not consistent with (b) the characteristics of the subject population being 
studied including the expected natural progression of any underlying disease, disorder or condition any 
predisposing risk factor profile for the adverse event. 
 
Serious Adverse Event (SAE) – Any adverse event occurring that results in any of the following outcomes: 
• 
death  
• 
a life-threatening adverse event (real risk of dying) 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly 
• 
requires intervention to prevent permanent impairment of damage 
 
Attribution - The following are definitions for determining whether an adverse event is related to a medical 
product, treatment or procedure: 
• 
An adverse event is “related or possibly related to the research procedures “if in the opinion of 
the principal investigator, it was more likely than not caused by the research procedures. 
• 
Adverse events that are solely caused by an underlying disease, disorder or condition of the subject 
or by other circumstances unrelated to either the research or any underlying disease, disorder or 
condition of the subject are not “related or possibly related.”  
• 
If there is any question whether or not an adverse event is related or possibly related, the adverse 
event should be reported. 
 
The Cancer Consortium Expedited Reporting Form should be completed for all adverse events that meet 
the expedited reporting requirements. The AE form should be faxed to the IRO at (206) 667-6831. All 
available information should be submitted. 

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Study-Specific Adverse Event Capture and Data Safety and Monitoring Plan 
Based on previous similar research with internet-based behavioral treatment conducted with survivors who 
have recovered from acute treatment effects and are living independently, this study is not expected to have 
Serious Adverse Events (SAE).  We will contact and collect data from participants at baseline, 6-weeks, 3 
months and 12 months.  We plan ongoing recording of adverse events for each participant, each reviewed 
by the PI within 7 days.  Any SAE will be immediately reported to the PI and the IRB according to 
requirements in the standard Fred Hutch DSMP.  As Coordinating Center, Fred Hutch will complete the 
Fred Hutch/UW Cancer Consortium Expedited Reporting Form for all adverse events, including those 
associated with participants enrolled from the participating consortium centers.  Ad hoc meetings will be 
called by the PI for any SAE, for two similar Adverse Events, or at any time by any other study staff or 
investigator for a data or participant safety concern.  A physician member of the research project will provide 
the medical monitoring for all adverse events.  Adverse events and SAE will be reviewed annually by the 
Fred Hutch standing Data Safety and Monitoring Board and Institutional Review Board in addition to the 
immediate reviews for SAE just described. 
 
The Study Coordinator continually monitors patient report data and prepares weekly updates of project 
activity for the investigators.  Risks related to the study that are expected or seen previously in similar 
studies include increased distress, complaints that the study material makes the participant feel worse by 
reminding him or her of problems, or complaints that assessments are too long.  Immediate contact is made 
with a participant and psychological support is available if any complaints are received.  Historically, with the 
prior internet sites implemented with N =1336 participants for R01 CA112631 and with N=1087 participants 
for R01 CA160684, none of these events have been serious and all have been resolved immediately with 
discussion or withdrawing the participant from the study. Serious adverse events which could possibly be 
related to the study include: a) complaints of intrusiveness or violation of privacy from the study (not just 
choosing to drop out of the study), b) anger, threats of harm or legal action against the study or a person, c) 
hospitalization for depression or anxiety, or d) physical harm as a result of a participant’s health care 
provider following the screening guidelines and ordering a test that causes the participant harm. 
 
The following steps will occur in documenting adverse events for this study: 
1. For any adverse event that is Serious, Unexpected, and Possibly Related to the study, the Investigator, 
or other study personnel who first becomes aware of the event will complete the Adverse Event form 
and will fax it to the PI, Dr. Baker within 48 hours.  FAX:  206-667-4356 (confidential secure fax).  If Dr. 
Baker is unavailable, Dr. Jean Yi, as Project Director, will perform her activities. 
2. The PI together with the investigator(s) who observed or reported the adverse event will assess causal 
relationship between the study procedures and the adverse event.  They will also assess severity at this 
time.  This will be done within 48 hours after notification of Serious Adverse Events, and within 7 days 
for all other adverse events.   
At this time, the PI will define a Response Plan for follow-up of the adverse event, determining: 
0 = No further response to the participant is needed. 
1 = Investigator told of event should follow-up to assure event has been adequately treated. 
2 = Further recommendations need to be offered to the participant and who will follow-up to provide 
these recommendations. 
3 = Additional treatment is needed, treatment recommendations are defined and an Investigator is 
designated to facilitate finding treatment if the participant is willing. 
4 = If participant or other person’s safety is in question, the PI/Project Director will determine whether 
a treating physician needs to be contacted to maintain safety.  If so, an Investigator will be 
designated to make that contact and to follow-up to determine the outcome. 
A notation will be made as to whether the adverse event resulted in the patient terminating the study. 
3. The PI or Project Director will complete an SAE form and fax it to the Fred Hutch DSMB and IRB within 
48 hours of receipt of the form and within 7 days of when the event becomes known.  
4. Within 7 days of any non-serious adverse event during the study, the Investigator or study personnel 
observing or first being told of the event will fill out this form and fax it to the Project Director. 

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5. At each weekly team meeting, a regular agenda item will be to review Adverse Events.  Documentation 
of no events or the nature of events will be included in team meeting minutes.  Adverse Event forms will 
be sent to all site PIs and their Study Coordinators for their use, although we do not expect AEs from 
contacting the survivors for participation.  Adverse Event forms will be retained, tallied and reported 
annually to appropriate agencies by the Study Coordinator. 
6. 
All Adverse Event Forms and SAE will be reviewed annually by the Fred Hutch standing DSMB.  At 
this time, they will prepare an adverse events summary to send to all Investigators and in annual reports.  
To reduce the likelihood of a similar occurrence the PI will schedule further discussion between staff if an 
adverse event is related to the study and is grade 2 or higher.  This plan, as well as a summary of adverse 
events and copies of the SAE forms completed since the last renewal, will be reported to the DSMB, IRO 
and NCI program officer annually.  Forms will then be filed with the patient’s confidential data, without 
identifiers. 
 
 
11.0  DATA CONFIDENTIALITY 
 
Only code numbers will be used on data.  Only staff who have been trained in human subjects protection 
and have signed confidentiality statements will have access to study information.  All hard copy data is 
stored in locked file cabinets in locked offices.  All data will be locked and password or keycard protected at 
all times.  All computerized data files will be password protected with passwords requiring regular updating.  
All clinical computing internet-related electronic data will be maintained on a secure web fileserver with 
backup and protection against unauthorized access, as with other computer databases.  Access to the 
database and programs will be controlled through requirements for unique accounts and passwords.  
Passwords will have a limited expiration life and will need to be reset quarterly for continued use.  The 
contents of the secure web server including program source code, web site information and data will be 
written to backup media daily.  Additionally, the study will have a secure online site, using the Clinical 
Oncology Research Entrance (CORE), for file and data sharing with Clinical Data Systems and Clinical 
Research Data Systems and across transplant centers. 
The Clinical Data Systems department will provide server security.  All electronic data will be maintained on 
a secure internet fileserver with backup and protection against unauthorized access.  Access to the 
database and programs will be controlled through requirements for unique accounts and passwords.  The 
contents of the secure internet server including program source code, internet site information and data will 
be written to backup media daily.  All hard copy data will be stored in locked file cabinets in locked offices, 
without personal identifiers. 
 
12.0 STATISTICAL CONSIDERATIONS AND DATA MANAGEMENT 
 
Projected Target Accrual for Randomized Study 
ETHNIC AND GENDER DISTRIBUTION CHART 
 
Table 2.  Anticipated/Planned Enrollment for Entire Randomized Study* 
Number of Participants (must provide exact numbers. i.e. no range) 
 
 
Non-
Randomized 
Participants* 
Ethnic Categories 
Sex/Gender 
 
 
Females 
Males 
Total 
Total 
Hispanic or Latino 
15 
15 
30 
6 
Not Hispanic or Latino 
242 
240 
482 
144 
Ethnic Categories: Total of All Participants* 
257 
255 
512 
150 
 
Racial Categories 
 
American Indian/Alaska Native 
3 
2 
5 
3 

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Design  
Enrollment.  We expect to approach 1358 potentially eligible survivors who are between 2-5 years after HCT.  
Of these, 100 will be run-in approaches with a projected 20 enrolled and randomized, but not included in 
analyses.  We project enrolling an additional N=492 eligible for a two-arm randomization to reach the sample 
sizes needed for each of the two primary endpoints.  An additional projected 100 are expected to register and 
consent for the study, but either not complete baseline assessment required for randomization or to not be 
eligible for randomization after baseline assessment because of treatment in the past two years or other 
exclusion criteria.  They will be given access to the INSPIRE site as a courtesy.  We expect another group of 
50 participants will consent but will not be eligible for randomization due to incomplete baseline assessment.   
Randomization.  Those with one or more targeted complications will be randomized to one of 2 arms (Group 
1).  Those without targeted complications will be separately randomized to one of 2 arms (Group 0).  We 
expect approximately  305 will be eligible for Group 1 randomization and inclusion in one or more of the 
analyses of the 2 primary outcomes.  To have sufficient power for each of the two primary endpoints, we will 
need to enroll 197 participants for the elevated distress outcome and 239 for the cardiometabolic non-
adherence. Participants who do not qualify for analysis of either primary endpoint (Group 0) will be 
important for inclusion in secondary analyses and will also be randomized to intervention vs. control arms.  
Based on our experience in the previous internet grant, we project a loss of about 28% in the course of the 
study implementation from consent to 12-month assessment, 8% from mortality or severe medical 
problems.  With 305 participants randomized to Group 1 for the primary analyses, this provides sufficient 
power for aims 1, 2, 3 and secondary analyses. 
 
Data Management  
We anticipate limited missing data and out of range responses by using the internet-based assessment, with 
phone calls to check with non-responders and mailed short-forms completed if necessary, as was the case in 
our previous research.  We have established a minimum, abbreviated set of forms that provide primary and 
secondary outcomes (CTXD, HCA, PHQ-8).  Assessment programming will set parameters for allowable 
responses and will return responders to items either missed or outside range, with an option to click a ‘choose 
not to respond’ box.  Validity checks will also be programmed to flag responses that are markedly inconsistent 
and may be invalid.  Outliers will be identified and sent to the Dr. Yi and the mPIs to determine whether clinical 
response is needed.  The mPIs will be notified and will contact a participant if validity seems questionable.  
They will assure that the participant personally completed the items and is cognitively capable of responding.  
In the past this has occurred only rarely, less than 1% of the time.  A second level of flagging will occur when 
depression responses indicate severe depression, as we expect 2% of assessments.  In these cases, the 
Project Manager will notify Dr. Yi.  The Project Manager’s data will be coded without names and Dr. Yi will 
decode these.  
Programming will provide for calculation of summary scores and data will be routinely downloaded to a project 
database.  The Statistician will examine distributions for normality (e.g., outliers, skewness) and conduct 
appropriate transformations or category coding if distributions are non-normal.  When data cleanup is 
complete, all files will be merged into a project database.  The project database and all data collection, 
analysis, and storage will be maintained at the Coordinating Center.  No study data will be maintained at the 
consortium sites. 
 
Endpoints  
Asian 
6 
6 
12 
2 
Native Hawaiian or Other Pacific Islander 
2 
2 
4 
0 
Black or African American 
16 
10 
26 
11 
White 
230 
235 
465 
134 
Racial Categories: Total of All Participants * 
257 
255 
512 
150 

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The primary endpoints to be evaluated for the above hypotheses are CTXD (distress) and HCA-cardio.  The 
primary and secondary endpoints for the study will be defined as binary outcomes.  Participants will qualify 
for analysis of a particular endpoint if they meet eligibility at their baseline response for that endpoint (CTXD 
≥0.9 or HCA-cardio<80% [primary endpoints], or HCA-cancer <80% [secondary endpoint], PHQ-8 score 
>10).  Some participants will contribute to both primary endpoint analyses, and others to none or one .  
Similar conditional analyses will be carried out for the secondary endpoints. Stepped-care telehealth will be 
introduced based on PRO assessed at 6-weeks, then short term outcomes will be assessed after 3 months 
and delayed or sustained effects will be assessed at 1 year.  
 
Primary Hypothesis  
Aim 1: Among HCT survivors with poor health care adherence to cardiometabolic or subsequent 
malignancy surveillance and/or elevated cancer-related distress, determine the impact of a patient-centered, 
self-management stepped care program compared to an active control group provided access to HCT 
survivorship best practices. 
Hypothesis 1: Participants with elevated cancer-related distress or poor health care adherence who receive 
the stepped care program will report reduced distress, and improved health care adherence for 
cardiometabolic or subsequent malignancy surveillance at 12 months when compared to controls. 
 
Secondary Hypotheses 
Aim 2: Determine characteristics of intervention participants who require telehealth stepped care at 6-
weeks. 
Hypothesis 2: Characteristics of intervention arm participants at the 6-week  interim assessment who 
require telehealth stepped care because they 1) do not meet criteria for adequate knowledge of 
cardiometabolic risks, or 2) do not report improved distress, or 3) have not logged in to the online program 
will include those with higher depression or distress scores at baseline, more health care barriers at 
baseline, age 70+ years, male sex, people of color, lower income and education. 
Aim 3: Determine resources that would be needed to sustain the intervention as a national HCT 
survivorship program if implemented through the CIBMTR//NMDP.  
 
Primary Endpoint Tests of the Specific Aims  
Hypothesis 1  
Participants with elevated cancer-related distress or poor health care adherence who receive the 
stepped care program will report reduced distress, and improved health care adherence for 
cardiometabolic surveillance at 12 months when compared to controls. 
 
Power Calculations  
As described in Table 3, we expect to enroll a total of 492 subjects in order to attain the 197 and 239 
participants needed to meet eligibility criteria for Group 1 randomization and inclusion in the intervention 
vs. control arm analyses of the 2 primary outcomes: dichotomous CTXD and cardiac HCA outcomes, 
respectively (some will be eligible for more than one).  Among these, we estimate that 71 and 86 per 
arm will be available for analyses after the 12-month evaluation, respectively.  Assuming control arm 
rates of events similar to or higher than those observed in the preliminary data from the INSPIRE study, 
these numbers of participants will allow us to detect a minimum relative risk of success for the 
intervention arm vs. the control arm of 1.9for the CTXD and for the HCA-cardio endpoints, with 80% 
power and two-sided α=0.025 for each comparison (α=0.05/2 = 0.025 to conserve overall α=0.05).  For 
evaluation of the continuous versions of the outcomes, we will have at least 80% power to detect a 
minimum effect size of 0.52, and 0.47 for the CTXD andHCA-cardio outcomes, respectively (α=0.025 for 
each). 
Table 3. Sample size calculations for Aim 1 primary outcomes, 80% 
power 

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Analysis Plan for Hypothesis 1  
The primary endpoints to 
be evaluated for 
hypothesis 1 are distress 
score (CTXD) and the 
proportion of HCA-cardio 
within the past 12 months 
as reported on the HCA 
and will be defined as 
binary outcomes.  
Participants will meet the 
primary endpoint for lack of 
distress if they score <0.9 
on the CTXD.  They will 
meet the HCA-cardio endpoint if their percent of recommended screenings obtained within the past 12 
months is ≥80% .  The number and pattern of missing variables will be summarized and assessed to 
understand potential biases.  If attrition is greater than 10% before the 12-month follow-up, we plan to 
utilize multiple imputation of the primary outcome and to carry out sensitivity analyses of the impact of 
missing data on the comparisons between study arms.[173] 
For Hypothesis 1, the two primary endpoints, evaluated at the 12-month time point among the subjects 
identified at baseline as impaired for that particular endpoint criteria will each be compared between 
study arms as intent to treat analyses using standard logistic regression analyses, adjusted for cancer 
center and utilizing a two-sided α=0.025 level of significance to preserve type I error at 0.05 overall for 
the two primary endpoints.  If other factors appear to be imbalanced between study arms, we will adjust 
analyses for those factors.  Secondary analyses will evaluate depression alone, a PHQ-8 score >10 
(essentially a subset of those with distress) and HCA-cancer in a similar manner as carried out for the 
primary endpoints.  Continuous versions of the tests comprising the primary and secondary endpoints 
using linear regression models as well as adjusting or stratifying on engagement with the intervention 
(viewing at least 3 pages of the online program or completing telehealth calls) will also be carried out.  
Assumptions regarding normality of the outcomes will be assessed, although examination of outcomes 
in preliminary data suggests this is a reasonable assumption, with no significant skew in the 
distributions.  If assumptions are not met, appropriate transformations will be implemented or alternative 
methods explored (e.g. non-parametric methods). 
 
Hypothesis 2 
Characteristics of intervention arm participants at the 6-week interim assessment who require telehealth 
stepped care because they 1) do not meet criteria for adequate knowledge of subsequent malignancy  
and cardiometabolic risks, or 2) do not report improved distress, or 3) have not logged in to the online 
program will include those with higher depression or distress scores at baseline, more health care 
barriers at baseline, age 70+ years, male sex, people of color, lower income and education. 
 
Analysis Plan for Hypothesis 2 
Among subjects in Group 0 and Group 1 intervention arms, we will define the endpoint as a binary 
indicator of whether the individual required telehealth stepped care at the 6-week time point.  We plan to 
use generalized linear models to evaluate associations between patient characteristic variables and 
likelihood of stepped care.  Variables to be examined include age (<70 vs. 70+ years), sex, 
race/ethnicity (White non-Hispanic vs. Non-White or Hispanic, income (<$40,000 vs. $40,000 per year) 
and education (college graduate yes/no), PHQ8 depression >16, and Barriers to HCA > 0.45. The need 
for telehealth stepped care is not likely to be a rare event (rare being <10%) and thus odds ratios from a 
logistic regression model would not be good approximations of the relative risk (RR).  Therefore, rather 
 
CTXD 
HCA-
Cardio 
 
Enroll/Consent/complete baseline 
492 
492 
 
T1: Eligible for specific endpoint 
197 
239 
 
3 mo. voluntary withdraw or 
mortality/illness (4%) 
[8] 
[10] 
 
3 mo. non-responders, able to 
respond at 12 mo. (15%) 
[30 eligible 
for T4] 
[36 eligible 
for T4] 
 
T3: 3 mo. completers (81%) 
160 
194 
 
T4: 12 mo. potential cohort 
189 
229 
 
12 mo. voluntary withdraw or 
mortality/illness (5% of T4) 
[9] 
[11] 
 
12 mo. non-responders (20% of T4) 
[38] 
[46] 
 
12 mo. completers (75% of T4, 
72% of T1) 
142 
[71/arm] 
172 
[86/arm] 
 

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than logistic regression we will likely use a log-link with Poisson error structure and robust sandwich 
variance estimates to directly estimate the more interpretable RR.[173]  A multivariable model will be 
established using single-variable and step-up and step-down procedures with a liberal p-value for 
inclusion in the model (p<0.2).  Factors identified as significantly (p<0.05) associated with the need for 
telehealth stepped care will be examined and based on the magnitude of the RR estimate and the 
prevalence of the particular patient characteristic, we will similarly examine indicators of response to the 
telehealth care based on continuous primary endpoints in that subgroup.  This will establish a profile of 
types of survivors for whom modified approaches to care may be beneficial.  
 
Aim 3 and Plan for Aim 3 
Determine resources that would be needed to sustain the intervention as a national HCT survivorship 
program if implemented through the CIBMTR/NMDP. 
This is a descriptive aim defining costs and resource requirements.  Data relevant to resource utilization 
(costs) and methods of collection are described in section 8.3 Cost and Resource Tracking.  All costs 
associated with the intervention and, separately, the control arms of the study for the Group 0 and 
Group 1 subjects in the study will be summed and standardized to per person costs.  We will use these 
amounts to calculate an incremental cost ratio for the online intervention program and telehealth 
intervention component compared to the control cost, similar to the method described by Mandelblatt et 
al.[171, 172]  The costs of maintaining the various components of the program, relative to their use, will 
be calculated separately for those in the Group 0 and 1 intervention arms, specific to maintaining the 
social media site, the internet program, and the telehealth calls (Group 1 only) relative to the number of 
participants using those components among intervention participants. 
 
Secondary Analyses  
Secondary endpoints will include depression, process measures describing internet study reach and 
utilization, as well as outcomes of knowledge of survivorship needs.  We will compare secondary outcomes 
knowledge of health care needs between study arms using similar analytic methods as for the primary 
outcomes (both binary and continuous outcomes).  We will also carry out subset analyses within stratum 
defined by the degree of utilization of the resources (i.e. more than one page viewed of internet site – see 
below for alternate definitions), and receipt of the phone calls if designated, to evaluate whether, among 
“users”, the tailored intervention has stronger effects. 
Further analyses will identify risk factors for disparities in survivorship HCA in HCT survivors. Study reach, 
adoption and attrition process measures will be reported descriptively.  
Primary analyses will be based on 12 month outcome measurements, but we will utilize the 3 month time 
point in secondary longitudinal analyses modeled after those carried out in DuHamel et al.[30]  Additional 
secondary analyses will include evaluation of the impact of the internet intervention on continuous versions 
of the primary endpoints, but among all participants randomized, including those not meeting criteria for 
inclusion in primary analyses.  This will provide estimates of the impact of study intervention on an 
unscreened population which would be a likely dissemination methodology. 
 
12.9 Process Descriptive Analyses 
Evaluation of the telehealth self-management calls will be based on 1) fidelity scored from audiotape 
reviews, 2) coach ratings, 3) completion rates of scheduled calls and 4) completion of action plans, and 5) 
barriers identified during calls.  Additional descriptive analyses will be conducted on the process elements 
defined in section 8.4 Process Measures. 
 
 

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13.0 TERMINATION OF STUDY 
 
Survivors in the intervention group will complete the intervention approximately 12 months after beginning 
(i.e., the date the patient received notification of randomization and website access).  After completing the 
12-month assessment, they will receive notification that they have completed participation in the study.  
Survivors will continue to have full access to the website after their official study participation has ended 
until the end of the study. 
Survivors in the control (delayed internet site access) group will have full internet program access from the 
time they complete the 12-month assessment until the end of the study. 
Survivors may withdraw from the study whenever they request to do so. 
 

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