Improved Behavioral Outcome in Allogeneic Hematopoietic Stem Cell Transplant Patients by Reducing Caregiver Distress: Behavioral and Physiological Evidence
Phase: NA
Conditions: Hematopoietic/Lymphoid Cancer
Sponsor: University of Colorado, Denver

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PROTOCOL #: 13-2639
(Use Protocol Manager on the COMIRB Website)
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  303-724-0990
Version Date: December 9, 2016
Project Title: Improved behavioral outcome in allogeneic hematopoietic stem cell transplant 
patients by reducing caregiver distress: Behavioral and physiological evidence
Principal Investigator: Mark L. Laudenslager
Co-Investigators: Teri Simoneau
Peter McSweeney
     Susan Mikulich-Gilbertson
Kristin Kilbourn
     Benjamin Brewer
Jonathan Gutman
 
I. Hypotheses and Specific Aims:
Patients receiving an allogeneic hematopoietic stem cell transplant (HSCT) undergo a demanding 
conditioning protocol. In contrast to cancer treatments using standard-dose chemotherapy, radiation, and/or surgery, 
treatment protocols for HSCT are more intense and life threatening. Following transplantation, patients are at 
increased risk for graft versus host disease (GvHD). To ensure adequate support, monitoring and safety, allogeneic 
HSCT patients are required to have a caregiver  available 24/7 for at least the first 100 days following 
transplantation and occasionally longer if complications arise. Allogeneic caregivers assist with a complicated 
medical procedure with 70% patient survival. The patient’s quality of life (QOL) is dependent on the quality of care 
provided by their caregiver. Caregiver distress impacts the quality of care they provide and thus patient QOL.
 
We showed that a behavioral intervention for caregivers of allogeneic HSCT patients reduced caregiver 
distress. A gap remains with regard to evaluating intervention impact on patient QOL. During the first 100 days, 
patients may be poor targets for behavioral intervention due to significant fatigue and debilitation. Carry over to 
patients as improved care may derive from caregivers participating in supportive programs. Patient and caregiver 
dyads will be randomized to either treatment as usual (TAU) or “fone” PsychoEducation and Relaxation (fPER) 
which provides a combination of face to face sessions and Smartphone video chat when a caregiver is unable access 
the clinic to meet with an interventionist. fPER caregivers will receive a biofeedback device for stress management. 
225 dyads will be randomized from 2 sites (private and university based) and followed for 6 mo. following 
transplantation. Specific aims are:
Hypotheses:
Primary hypotheses: Patients whose caregivers receive fPER will have improvements in FACT-BMT compared to 
TAU.
Secondary hypotheses: Caregivers who receive fPER will have reduced distress compared to TAU.
Specific Aims:
Aim 1: Create a Community Advisory Board (CAB) consisting of allogeneic HSCT patients, caregivers, 
blood cancer oncologists, support staff and study investigators to provide input.
Aim 2: Assess patient QOL following an allogeneic HSCT using the FACT-BMT as the primary patient 
outcome. Patients whose caregivers receive fPER will have improved QOL compared to caregivers 
assigned to TAU. 
Aim 3: Test the impact of fPER on a caregiver composite distress score (encompasses depression, anxiety, 
and stress) as the primary caregiver outcome. Caregivers receiving fPER will have reduced distress.
COMIRB
APPROVED
07-Mar-2017

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Aim 4: Assess biomarkers of allostatic load in patients prior to transplant and caregivers during the 
transplant process using novel biomarkers (hair cortisol and telomeres). fPER will be associated with 
reduced allostatic load in caregivers compared to TAU. Patient hair cortisol collected only before transplant 
will relate to QOL at intake.
Deliverables include 1) developing evidence supporting improved patient QOL associated with 2) minimizing 
caregiver distress as well as 3) a manualized intervention, fPER, based on stakeholder input and oversight 
available for dissemination. 
II. Background and Significance: 
A.1. Impact of the Condition on the Health of Individuals and Populations (Criterion 1)
Treatment protocols for patients receiving allogeneic hematopoietic stem cell transplants (HSCT) are 
more intense and life threatening than other forms of cancer treatment1-4. Following transplantation, HSCT 
patients are at increased risk for a variety of physical side effects, including infections and graft versus host 
disease (GvHD).2,4 Patient quality of life (QOL) is substantially reduced following transplantation.5-10 
Allogeneic HSCT patients require a caregiver 24/7 for the first 100 days and occasionally longer following 
transplantation to ensure adequate support for the patient.11,12 A primary role of the caregiver is to monitor the 
patient closely for infection, fevers, and features of GvHD as well as to track complex medication regimens, 
deliver specialized food preparation, and provide transportation to appointments or emergency room visits.4,12 
Patients and their caregivers are required to move to within 30 min. of the transplant center during the 
transplant recovery process. Our recent experience working with this group of patients indicated that over 23% 
of the transplant recipients lived out of state and 46% of all allogeneic HSCT transplant patients had to relocate 
to temporary housing near the clinic.13 In addition to decreased patient QOL, the caregiver is at significant risk 
for a number of psychosocial problems.14-18 Caregiver distress, in turn, is likely to impact the quality of care 
that a caregiver provides for their patient. In spite of these issues, there is a gap in interventions focused on 
coping with stress by the caregivers,19-22 especially allogeneic HSCT caregivers.13,14,23,24 Studies of caregiver 
interventions to mitigate distress have been plagued by small samples, lack of randomization, short follow up 
periods, problems with blinding, assessment limitations, failure to measure health services utilization by 
caregivers, absence of biomarkers of caregiver well-being, and caregiver study attrition25-27 and NONE have 
focused on the impact on the patient’s QOL. Therefore, a significant gap in the evidence base exists with regard 
to effective caregiver interventions and their impact on the patients’ QOL and medical outcomes. The present 
application is pertinent to Criterion 1 as allogeneic HSCT patients have a high burden of chronic medical issues 
following transplantation with reliance on a caregiver for tangible, informational and emotional support.
Care for ill and/or disabled loved-ones has been increasingly assumed by family and close friends due 
in part to changes in our health care systems.28 In 2009, roughly 42 million caregivers in the US provided an 
unpaid contribution to health care neighboring $450 billion dollars which exceeds Federal Medicaid spending 
over 8 fold29. This represents an estimated 40,300 million hours of care29 most often provided by immediate 
family members. Thus, caregivers are a fundamental component in cancer survivorship30: a large component 
of patients’ health and welfare rests with the caregiver. However the stress of caregiving brings increased 
psychological and medical morbidity to the caregiver30-34. Depression in spousal cancer caregivers may exceed 
depression in the patients themselves35 raising the question of “who is the patient?”36-38 There are bidirectional 
influences between the patient and caregiver such that the moods and health of one influence the moods and 
health of the other. Much like putting on your own oxygen mask first before assisting the passenger beside 
you, as instructed by flight attendants, caregivers need to prioritize their self-care needs in order to ensure that 
they can adequately care for their loved-one. 

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How would an efficacious caregiver intervention impact patient QOL? What would that intervention 
look like? Caregivers are faced with a demanding responsibility. We approach caregiver distress from a stress 
and coping framework.39,40 Suggestions for caregiver interventions have included: 1) education regarding patient 
illness, 2) psychosocial intervention that will strengthen perceived control, and 3) promotion of enhanced self-
care.26 Former US Surgeon General, Richard H. Carmona, suggested a “Rx for caregivers” that included 
attending to depression and anxiety, identifying sources of support, reducing stress, taking care of one’s 
physical health, and providing education regarding the illness.41 To date, most caregiver interventions have not 
completely addressed the caregiver Rx, particularly in regard to HSCT caregivers and more specifically 
allogeneic caregivers. 
With this background, our group recently 
completed a randomized control trial (RCT) of an 
intervention for allogeneic HSCT caregivers with 
promising results. Our eight session, one-on-one 
intervention, PsychoEducation, Paced Respiration, 
and Relaxation (PEPRR),23 addressed all aspects of 
the Surgeon General’s Rx. We found at the end of the 
100 post-transplant period that caregiver perceived 
stress (a measure of sense of control and the primary 
outcome), depression, anxiety, and a summary distress 
score were significantly reduced in caregivers 
receiving PEPRR compared to Treatment as Usual 
(TAU) with effect sizes ranging from .39 - .66. 
However patient assessments were limited to medical 
chart reviews and the Short Form 36 health 
questionnaire (SF36)42 obtained 1, 3, 6 and 12 months post-transplant. Based on a completers analysis at 6 
months post-transplant, there were no differences (p=.36) between TAU (n=35) and PEPRR (n=35) on the 
SF36 physical scale which fell below population norms in both groups. However in this small sample we noted 
a trend for the patient SF36 mental score to be slightly higher (e.g., better score, p =.11) in the PEPRR group 
compared to TAU as shown in Figure 1. One half of a standard deviation (1 SD = 10 points on the SF36) 
between the two groups is considered a meaningful clinical difference.43 In spite of continued diminished 
physical function, the patients whose caregivers received PEPRR reported mental health scores in the normal 
range for healthy people, while those in TAU were lower. Thus our initial success with PEPRR for caregivers 
has pointed to two important paths: 1) the need for verification of changes in patient QOL and 2) extending 
accessibility and reach of the intervention to include caregivers who might not have been eligible for 
participation because they lived out of the geographic region of the transplant program.
A.2. Innovation and Potential for Improvement Based on Our Research (Criterion 2)
The initial RCT provided important insights regarding ways of enhancing the intervention based on 
caregiver and interventionist feedback. A caregiver intervention must be acceptable to the caregiver who may 
not always focus on his/her own needs and often feels quite overwhelmed. We propose to take our intervention 
for allogeneic HSCT caregivers,23 PEPRR (pronounced “pepper”), and apply novel approaches to enhance its 
reach to stakeholders. In enhancing PEPRR’s utility and usability we drew innovatively from concepts of web 
design44 to create “fone–PER” or fPER (pronounced “fepper”) which will incorporate Smartphone technology 
to achieve part of this goal. “Utility” in web design refers to “does the user (e.g., caregiver) get what they want 
out of a system?” and “usability” refers to the user’s perceived ease-of-use of a system.44 We seek to optimize 
both dimensions. We have amassed considerable information during the initial trial of PEPRR regarding utility 
and usability from caregivers based on exit questionnaires as well as comments made during PEPRR sessions. 
Using these webpage design concepts, caregivers were essentially engaging in a User Testing Interchange 
regarding the utility and usability of PEPRR during its early testing. For optimal results, both utility and 
usability are important as most users will not continue to use a system that does not meet their needs, no matter 
how easy the system is to use (utility). Conversely, most users will not persist with a system that is too complex 

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or frustrating (usability), even if remarkable results are promised. User testing is an iterative process whereby a 
product (in this case the intervention) is repeatedly designed, tested, and redesigned to maximize both utility and 
usability. We feel this is an innovative conceptualization of developing a behavioral intervention. We asked 
caregivers to “think aloud” as they participated in PEPRR. As they learned to manage stress associated with 
caregiving through PEPRR, we simultaneously asked about their experiences and we learned from them what 
worked and did not work in PEPRR13 while maintaining intervention fidelity. Thus we relied heavily on 
caregiver input to develop fPER. For example, we learned that a biofeedback device used in PEPRR, the 
RESPeRATE,45 was viewed as “something more to do” and not adding an effective coping behavior. This was 
not our intention. Subjects found it cumbersome and simply stopped or reduced use after 4-6 weeks in the 12 
week trial. An alternative biofeedback device that is less obtrusive and easier to use will be tested in fPER in 
anticipation of larger community deployment of this support program.
The initial version of PEPRR, based on the stress and coping model46, sought to enhance the caregiver’s 
perceived sense of control47-49 of their situation by providing various approaches to coping. PEPRR provided 
education about stress and its consequences as well as means for managing stressful situations using cognitive 
behavioral techniques.23 When reflecting on issues around stress and health, caregivers often reported at the 
beginning of PEPRR a very limited appreciation for the consequences of stress on their personal health and 
failed to utilize adaptive coping behaviors. While experiencing a special day with her loved one after completing 
PEPRR, a study caregiver wrote “… I breathed deeply and smiled. I was grateful for a moment’s peace and for 
a greater appreciation of the natural stress relievers that were everywhere…” (Chicken Soup for the Soul: Say 
Goodbye to Stress, 2012, p.41-42.).
To increase the utility and usability of fPER, we plan to implement several enhancements to the 
intervention prior to dissemination. For example, the previously used device-guided respiration apparatus 
(RESPeRATE) required about 25 min/day be set aside for its use 4-5 times each week. Reported barriers to its use 
included finding time (26%), did not like it (6.5%), or could not make it part of their routine (10%). Subjects 
adhered to study requirements over the first few weeks but this declined around the time the patient was 
discharged from the hospital, which would be consistent with the time that caregiving duties increased. A concrete 
example of increasing usability based on user testing will be to exchange the RESPeRATE with a simpler device. 
We will substitute the RESPeRATE with an easier device, the emWave250-52 (HeartMath, LLC) in fPER. The 
emWave2 is a small self-contained portable platform, smaller than a cellphone, for stress management which can 
be readily available to the caregiver when a stressor or challenge occurs. One simply places a finger on the 
emWave2 for less than 5 min while pulse information is collected and translated to a light indicator (red, blue, and 
green) as a sign of moving from a “stressed state” to relaxation using skills learned in fPER. This will improve 
the caregiver’s perceived sense of control.14 We are fully committed to being responsive to stakeholder input 
which we gained during and following the first RCT to ultimately increase utility and usability of fPER for wide 
dissemination to caregivers and thereby improve their care of their loved ones.
Since most people will own Smartphones by 2025,53 it is an opportune time for this technology to be 
incorporated into fPER in a manner that will facilitate caregiver contact and improve the likelihood of providing 
more fPER sessions. Although telephone interventions are not novel,54-59 they are represented by only a minority 
(20%) of caregiver interventions based on a recent meta-analysis.21 The advanced technology of smartphones 
continue to be poorly appreciated53 including their use for reminders via text messages, prompts for medication 
administration, appointment reminders, data collection, and a means to interact with support therapists visually 
and aurally using concepts of telemedicine.60-63 We propose to include the Smartphone as a new and novel 
enhancement to the intervention recognizing its role in the information age.64-67
78% of the caregivers requested additional support sessions for a variety of reasons including; a 
second transplant, continuing to experience high-levels of stress, or new stressors arose over time with the 
chronicity of their loved one’s side effects. One caregiver in the prior trial commented,”… I think a follow-
up session once we left Denver would have been helpful, even by phone…” reinforcing the need for 
additional support as well as developing an approach to provide support at a distance. Thus we have added 

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additional sessions to incorporate the requests of caregivers expressed in the initial study.  The capacity for 
distant interventions is critical as expressed by an allogeneic HSCT caregiver:
“…I haven't reached out to [clinic name deleted] directly for services yet because distance is a bit of an 
issue, especially with a small child…”
Statements specifically supportive of video chat sessions included “… video would not be the same as in 
person but better than a telephone…” and 
“…I prefer face-to-face but video would be a 
good substitute…” 
Looking specifically at the geographic 
locations (See Figure 2) of the distant 
caregivers (representing 46% of the study 
group) suggests that many caregivers live a 
significant distance from the clinic where 
follow-up services can be provided using 
Smartphone technology.
fPER will improve patient care by 
providing services previously unavailable to 
families who live outside immediate clinic 
reach, addressing a common problem for all 
HSCT programs. Our own observations 
suggest that in the peri-transplant period, 
allogeneic HSCT caregivers fall above 
population means and clinical cut-off scores 
on measures of stress, depression, and anxiety.14 Comparable stress in the patients is indicated in other studies.68 
By enhancing the caregiver’s coping skills as they enter this challenge, they can better serve the patient and 
themselves. In response to Criterion 2, using technology to increase utility and usability is the next step prior to 
multisite dissemination, implementation and wide-spread availability of this important intervention which we 
propose will have significant benefits on patient and caregiver mental health. Full dissemination of our 
intervention requires verification that the fPER program will improve patient QOL and caregiver well-being while 
enhancing caregiver program access, participation, retention, and generalizability.
A.3. Impact on Health Care Performance (Criterion 3)
Care for an allogeneic HSCT patient is inextricably entwined with the presence of a high functioning 
caregiver, but this is not without cost to the caregiver.14,15 The present study has direct relevance to Criterion 3 
because improvements in caregiver mental health will result in improved care for the HSCT patient during a 
highly challenging experience for both stakeholders. A caregiver’s comment after receiving PEPRR was “…it 
should be mandatory for all caregivers…” emphasizing this need. In support of Criterion 3 we propose that the 
availability of fPER will have a significant impact toward improving patient care and thereby their QOL by 
mitigating caregiver distress. In our prior research on caregivers, preliminary trends in mental health care 
services utilization were reduced for caregivers in the intervention group (other than care provided by the 
intervention). This reduction occurred during the 6 mo. period following transplantation when compared to 
TAU using a mixed models logistic ANOVA, month X intervention group interaction [p=0.057]. This suggests 
that PEPRR substituted for costly mental health services AND that PEPRR reduced perceived stress following 
the transplant. Furthermore, reducing potential participation barriers by improving access to the program and 
eliminating geographical barriers will increase the number of caregivers who can benefit from this psychosocial 
program which will lead to a positive impact on patient QOL.

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III. Preliminary Studies/Progress Report:  
Allogeneic hematopoietic stem cell transplant (HSCT) caregivers must be available 24/7 for the first 100 
days and often longer following a transplant. However behaviorally and more importantly medically healthy 
caregivers are essential for the best patient outcome. Few interventions for caregivers have been tested by 
randomized clinical trials (RCT). Our objective is to determine if a stress management intervention for allogeneic 
HSCT caregivers compared to self-care relying on resources of the transplant program (treatment as usual, TAU) 
would be associated with lower stress.  We designed a randomized control trial with intent-to-treat of an eight 
session manualized stress management intervention provided to caregivers following transplant. Subjective 
behavioral data collected longitudinally for 12 months using standardized instruments was entered blindly.  The 
HSCT caregivers were recruited from a community transplant program between November 2008 and April 2012.  
The study included a consecutively approached sample of 267 caregivers of allogeneic HSCT patients. 148 (mean 
age=53.5 years, 75.7% female) were randomized to a manualized intervention (n=74) or TAU (n=74).  101 
caregivers reached the three month follow-up with drop outs associated with patient and/or caregiver factors. The 
intervention included an eight session stress management program provided to caregivers by a social worker during 
the immediate post-transplant period that focused on learning about stress, changing role(s) of the caregiver, 
cognitive behavioral approach to managing stress, paced respiration with a commercial biofeedback device, and 
identifying resources.  A panel of questionnaires and physiological markers was collected from the caregivers five 
times over the course of one year beginning in the peri-transplant period.  The primary outcome measure was self-
reported perceived stress. Secondary outcome measures included depression, anxiety, caregiver burden, physical 
health, sleep, trauma and composite scores of these measures.  Groups did not differ at baseline. Controlling for age, 
the intervention resulted in significantly lower (p=0.039) caregiver perceived stress (primary outcome) at 3 months 
post-transplant (Mean=20.0, SD=1.0) compared to TAU (Mean=23.0, SD=1.0) with an effect size (ES) of 0.39.  The 
intervention group showed significantly better (p=0.019) scores on a secondary composite score that includes 
depression, anxiety, and other distress measures (Mean=-0.22, SD=0.13) compared to TAU (Mean=0.23, SD=0.13) 
with an ES of 0.45.  This study had limitations due to problems with low minority subject recruitment, logistics of 
collecting dependent measures when patients and caregivers moved out of the area, as well as missing data.  While 
needing further study within more settings, this approach is likely to improve caregiver well-being and potentially 
that of patients. 
IV. Research Methods
A. Outcome Measure(s):  
Patients with caregivers in fPER will show improved QOL and caregivers will show reduced distress as primary 
outcomes. Secondary outcomes will show improvements in patient comorbidities, depression and anxiety 
(patients and caregivers), and caregiver biomarkers of chronic stress.
Patient QOL is the primary outcome measure in this RCT, which will be complemented by secondary 
behavioral and medical outcomes of the patients. The rationale for this study is that QOL and mental health 
factors contribute to overall outcomes in a variety of illnesses including cancer.69-71 A variety of interventions 
directed towards patients have been shown to improve psychosocial and biological outcomes.72-76 
Unfortunately, during the early phases of the transplant process extensive participation by patients in 
psychosocial programs of any type is precluded due to physical debilitation.68 An indirect impact may be 
afforded by a focus on the caregiver. Improved caregiver self-care and enhancement of coping skills may lead 
to improved patient QOL via indirect avenues, e.g., the caregiver is better able to focus on the patients’ needs 
and care because the caregiver’s distress is reduced. Although a bidirectional relationship between patient and 
caregiver is implicitly understood, there is a relative lack of evidence that family and/or caregiver 
interventions impact patient outcomes thus representing a significant gap in the literature. Improved 

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Table 1. Study conditions and sample
sizes
Group
Condition Site 1 - UCH
Site 2 – CBCI
TAU +
Manual
37
75
fPER
38
75
Total
(225 dyads)
75
150
caregiver coping learned via fPER will have a significant impact on patients during a time of uncertainty, 
unpredictability and loss of control.
B. Description of Population to be Enrolled: 
450 total adult subjects (225 patients and their 225 
caregivers) will be randomized as pairs by permuted block 
into treatment as usual (TAU) or “fone” PsychoEducation 
and Relaxation (fPER). A total of 112 caregivers (distributed 
proportionally in relation to patient pool across the two sites 
and ethnic and racial category) will be randomly assigned to 
TAU and 113 to fPER after completing baseline assessments 
as shown in Table 1.  The expected age range of caregivers 
and patients is expected to 18-85 years of age. It is unlikely 
that anyone under the age of 21 will be a caregiver for an allogeneic HSCT patient and HSCTs are not 
performed for children by either program.  Should a younger caregiver present themselves, we will reevaluate 
the lower cut off. Although caregivers are expected to be generally healthy, we will exclude individuals who 
are taking steroidal medications for allergy or inflammatory disorders. These medications are most likely to 
confound the hair cortisol assessments.  Medication use by caregivers will be treated as a covariate in 
secondary analyses. Eliminating caregivers who use any medication(s) would skew the nature of the caregiver 
sample so that the subjects in the intervention would be only the very healthy. Such selection would distort 
the potential impact of the intervention on biomarkers and behavior for the population overall.
Patients: Inclusion criteria include: 1) receiving an allogeneic HSCT, 2) able to read and speak the English 
language, and 3) telephone access.  
Caregivers: Inclusion criteria include: 1) the person in the patient’s life who is primarily responsible for 
care decisions, emotionally invested in the patient’s care, provides instrumental care such as transportation, 
and available if randomized to the fPER group to participate in the majority of intervention sessions, 2) be 
able to read and speak the English language, 3) willingness to use a Smartphone, 4) absence of a serious 
medical condition likely to influence cortisol assessment in their hair, 5) alcohol consumption less than 2 
drinks/day, 6) no steroid medications, and 7) at least 18 years of age.
Patient and caregiver exclusion criteria 
include a history of a psychiatric illness 
unrelated to the HSCT within the past 
18 months. Children under the age of 18 
do not receive HSCTs in either 
program.
Collaborating Sites:  The two study 
sites include Presbyterian St. Luke’s 
Medical Center/Colorado Blood Cancer 
Institute (CBCI) – Site 1 and the 
University of Colorado Hospital (UCH) 
– Site 2. There are currently no other 
caregiver interventions studies offered 
at either site that would compete or limit 
subject availability for the present 
study.  Projected enrollment from each 
site over 27 mo. is given in the adjacent 
figure.

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C. Study Design and Research Methods:
Subject flow for fPER and TAU is indicated 
in Figure 4. Following consent (both 
members of the dyad must consent), patients 
and caregivers will complete a panel of 
questionnaires and provide a baseline hair 
sample. Only caregivers will provide blood 
samples for DNA, lymphocyte and plasma 
banking. After completing baseline 
measures, subjects will be assigned to 
treatment group by permuted block design 
known only to site coordinators (Brewer and 
Simoneau) and interventionists. The first 
intervention session for fPER assignment 
will begin as soon as possible after 
consenting prior to transplant. Collection 
time is anchored to the day of transplant as 
day 0 for statistical analysis. The subsequent questionnaire collections for both patients and caregivers will be 
at approximately +6 weeks and +3 and +6 months post-transplant. Hair and blood samples will only be 
collected post-transplant from caregivers at 3 and 6 months. Hair will be collected from the patients pre-
transplant and at +6 months post-transplant. For those patients who have previously been on either steroid 
medications or chemo prior to conditioning, this information will be recorded for this exploratory study of 
hair cortisol in the patients. These samples are collected for exploratory analysis only. Caregivers will 
provide hair samples on three occasions at baseline prior to randomization and three and six months after 
their patient’s transplant. Hair is removed from the posterior vertex of the scalp at a proximal level using 
thinning shears. This region is more resistant to hair loss in male pattern baldness (e.g., one of the last areas 
to be lost).  Cosmetically one cannot tell the hair was removed.  For subjects without adequate hair this will 
be treated as missing data. However the Laudenslager laboratory has developed an approach that permits the 
assay of far less hair (1/10 of most published reports) which allows for receding hair lines and shorter hair in 
males. 
At each phase, patients and caregivers will complete the same battery of questionnaires that includes the 
Center for Epidemiological Studies-Depression scale (CES-D), the perceived stress scale (PSS), Pittsburgh 
Sleep Quality Inventory (PSQI), and the State-Trait Anxiety Inventory (STAI).   Additionally the patient will 
complete the FACT-BMT each time while the caregiver completes the Caregiver Reaction Assessment 
(CRA). Both the patient and the caregiver will additionally complete a demographic questionnaire that 
includes questions regard age, diagnosis, income, and other standard questions regarding nutrition, health 
behaviors, and health services utilization. At study completion, an exit questionnaire will address each 
subject’s evaluation of the study and the group in which they were assigned. Each subject will be assigned a 
code number for de-identifying purposes at consenting and this number will be the only identifier on 
questionnaires. The confidential code sheet that identifies the subject’s randomized treatment group based on 
a permuted block design, subject name, and contact information will be kept in a locked cabinet as well as in a 
password protected secure data base.  After the randomization table is created by the biostatistician, this will be 
available only to Drs. Simoneau and Brewer.
Intervention groups
TAU. All patients and caregivers, regardless of randomization, are informed of what to expect during the 
transplant process and how to locate available support resources within each program. Patients and caregivers 

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are given information that is specific to their involvement in the transplantation process and recovery phase. 
Subjects randomized to TAU will be encouraged to participate in available support programs at their 
respective centers which are very similar between sites and include individual counseling as well as support 
groups. Due to the impact of our prior intervention on caregiver distress, we will provide each caregiver 
randomized to TAU a workbook prepared for someone to use without one-on-one sessions with a therapist.
fPER. Our User Testing dialogs provided a number of ideas for new approaches that will be incorporated into 
fPER. User Testing has indicated the time immediately before transplant to be a time of significant distress 
associated with anticipation and fear of the unknown. Many caregivers felt additional support after day 100 
would also be helpful when transplant program support generally declined though they were still dealing with 
post-transplant issues. To address these issues, fPER will begin prior to transplant (unlike the previous study 
where the first session often did not begin until more than two weeks after the transplant). The active treatment 
will be increased to 10 manualized sessions (from 8 in PEPRR) to include two additional sessions between 4-6 
months post-transplant. fPER will also include incorporation of Smartphone technology to make the 
interventionist available by video chat. Thus, fPER represents targeted modifications from the initial 
intervention with many enhancements and improvements that will enhance scheduling flexibility, improve 
retention and intervention completion rates, as well as improve outcome. Behavioral assessments will be 
collected prior to randomization, and at 6 weeks, 3 months and 6 months after transplant (anchored to the day of 
transplant as day 0). Blood samples from caregivers will be collected at the same time whereas hair samples will 
be collected every three months: baseline (patient and caregiver), 3 (caregiver) and 6 (patient and caregiver) 
months post-transplant. fPER sessions will be delivered either at the clinic during patient visits or via video chat. 
Each fPER session will be devoted to a separate topic with the goal of assisting the caregiver in the 
development and application of stress-management coping skills including learning problem-solving skills, 
identifying cognitive distortions, application of relaxation techniques, use of the emWave2, coping skills 
training, effective use of social support, and establishing appropriate goals. The intervention meets the needs and 
requests identified in User Testing. All caregivers in fPER will be provided a Caregiver Workbook that includes 
information about the session topics and homework assignments.
Briefly in order, the sessions will include: 1) Overview and introduction to stress management, 2) Stress 
and the mind-body connection, 3) How our thoughts can lead to stress, 4) Coping with stress, 5) Strategies for 
maintaining energy and stamina, 6) Coping with uncertainty and fear of unknown, 7) Managing changing 
relationships/communicating needs, and 8) Getting the support they need, modeled after a successful 
intervention for patient groups.93 Manualization is crucial for successful wider implementation.94,95 Sessions 9 
and 10 will provide booster sessions in which the interventionist will assess current challenges for the 
caregiver, provide review, and emphasize further coping skills training that might assist the caregiver in 
managing current stressors such as coping with the “new normal.” Intervention fidelity will be determined 
from DVD recordings made during sessions. Twenty percent of sessions will be randomly reviewed for 
adherence to an 8-11 item check list. In our prior RCT, overall fidelity (e.g., did the interventionist address 
each item?) was 96.4% across all sessions.
emWave2. Based on User Testing during the previous RCT, we learned that the previous biofeedback device, 
the RESPeRATE, was not uniformly accepted by all caregivers. Furthermore, the amount of utilization of that 
device was not associated with any of the behavioral outcomes at three months in the prior trial (in preparation). 
We will replace the previous device with a more convenient and user-friendly device, the emWave2 (Heartmath, 
Inc), for the fPER group. In brief, emWave2 is a small hand-held device on which the subject places their index 
finger or alternatively connects a simple sensor to their ear. Pulse information during this contact determines 
heart rate variability to provide visual indications of increased vagal tone or coherence (a sign of improved 
relaxation) using manufacturer’s terminology.52 It measures 8 X 4 X 1 cm and can be easily carried in one’s 
pocket or purse for ready availability. The time leading to increased vagal tone has been demonstrated in a 

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variety of subjects to shorten while using this device.50,51,96,97 The emWave2 is superior to the RESPeRATE on 
the basis of convenience associated with size and reduced burden based on set up and time required to achieve 
relaxation (less than 10 min versus 20-25 min.). This is not considered a medical device but rather an ancillary 
tool for stress reduction and personal growth according to the manufacturer and which has been commercially 
available for over 15 years.  
Smartphone. Based on User Testing during the previous trial, we learned that flexibility in intervention 
scheduling was central to ensuring that caregivers participated in the majority of sessions. In the first RCT, 
caregivers had difficulty making appointments or did not want to leave their patient during clinic visits for a 
session for fear of missing a doctor’s visit.13,23 Appointments were cancelled due to patient status changes, bad 
weather, as well as when the interventionist was sick and avoided exposing the caregiver to an infection. The 
Smartphones will easily overcome these problems. Telephone interventions59,98 as well as telemedicine are 
relatively new approaches to treatment but have been used successfully in rural settings.61-63 We will 
incorporate this modality through the use of Smartphones for video chat with caregivers when they prefer to 
hold a session from a distant location. For the previous study, 46% of the caregivers and patients were required 
to relocate. Some of these dyads were allowed to go home early and consequently the caregiver missed the 
later intervention sessions which can now be provided by fPER. Video chat will be recorded during the 
session by the interventionist using BSR Screen Recorder so that these sessions can undergo reliability testing. 
This information will be downloaded from the interventionist’s Smartphone immediately and transferred to a 
secure data base according to HIPPA requirements. Observations from our first trial indicate that many 
caregivers own a Smartphone; those who do not own a Smartphone will be provided one by the study along 
with a suitable Smartphone service contract for the duration of the study. They will also be provided with 
training on its use.
Smartphone enhancement. Smartphones will be used for sessions when the caregiver is unable to come to the 
transplant center. Caregivers will also receive training in the use of the Smartphone calendar app for scheduling 
their patient’s appointments as well as their own fPER sessions. Interventions using a study Smartphone will 
send scheduled session appointments reminders via text messaging to the caregiver’s Smartphone. No personal 
health information will be sent via text messaging. If the caregivers choose, we will upload any selected app to 
the subject’s Smartphone that could potentially “lighten their load” such as brief affirmations each day that are 
positive and reinforcing.
Table 1 (Patient):

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The following two tables outline the temporal sequence of procedures for the two caregiver groups.  
Table 2 (Voluntary Support Services or TAU):
Table 3 (Scheduled Individualized Training Sessions using fPER):
D.  Description, Risks and Justification of Procedures and Data Collection Tools:
Biomarkers of chronic stress
“Allostatic load” as conceptualized by McEwen and colleagues79,111-113 represents the wear and tear on the 
organism associated with maintaining allostasis (physiological balance) in the presence of a challenging 
environment such as associated with aging114 or created by caregiving115. Allostatic load markers116-118 are 
quite varied. Investigators have used a number of markers of cumulative stress including inflammation,118,119 
telomere length,90,92,120,121 and more recently the measurement of cortisol in hair.85,87,88,122 In general, allostatic 
load is associated with poor health123 including heart disease.124 We will assess allostatic load in this study.
Blood. As indicated in Figure 4, caregivers will provide a total of 3 venous blood samples collected by trained
phlebotomists through the course of the 6 month study. Each blood sample will be approximately 20 ml 
collected by venipuncture for lymphocyte isolation for telomere assays as well as plasma banking. Plasma will 
be banked at each time in the event new developments in assessing allostatic load for caregivers becomes 
available. Patients will not provide blood samples for the study. Blood pressure will be measured before each 

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blood draw and recorded. Blood samples will be transported to the laboratory in biohazard packaging at room 
temperature. Plasma will be removed after 
centrifuging at 1800 RPM for 15 min at 25oC. 
Supernatants will be stored in multiple aliquots in 1.4 
ml microcentrifuge tubes with o-ring seal caps at -
70oC. Each tube will be labeled with a subject code 
number that corresponds to an Access database 
inventory maintained for the study.  Hair cortisol. 
Repeated saliva collections as a marker of HPA 
activity can be taxing for subjects even when new and 
improved means for collection are applied.125 Hair 
cortisol provides a retrospective index of HPA 
activity87 (much like hemoglobin A1c reflects glucose 
control in diabetes126). Repeated collections of diurnal 
salivary cortisol were significantly correlated with a 
corresponding collection period for hair cortisol85 as 
shown for a combined sample of mothers in their third 
trimester (Figure 7). We have also found hair cortisol to be stress responsive and heritable127 as well as 
associated with behavioral phenotypes.86 We are excited about this innovative approach to objective assessment 
of allostatic load/retrospective stress reflected as HPA activation. As an exploratory measure, it will permit an 
assessment of patient retrospective HPA activity before the transplant and additionally continuously track HPA 
activity in the caregiver through the study. Patient hair will be collected twice due to the effect of transplant 
conditioning on hair growth. In some patients, previous treatments including steroid medications may make this 
not possible and as an exploratory measure this is acceptable. Cortisol will be measured as previously described85 
from hair samples collected from the posterior vertex region of the scalp using thinning shears leaving no 
noticeable change in appearance. Hair grows at approximately 3 cm/mo. We will assay the proximal 3 cm. by 
refined procedures for samples weighing less than 5 mg. In brief hair is ground, extracted, and processed by 
immunoassay (Salimetrics) with intra and inter-assay CVs less than 10%. We appreciate some males with 
balding or short hair cannot provide ideal samples but our assay allows for small samples corrected to length and 
the statistical approach also allows for missing data in a nonbiased manner when it occurs.
Telomere length (TL) and telomerase activity (TA). TL and TA are considered markers of aging.90 As a stress 
marker, telomere length is reduced in caregivers.90,121,128,129 However an important unanswered question is: “Are 
differences in telomeres reversible by behavioral interventions92 such as fPER ?” Recent collaborative pilot 
studies have included analyses of telomere length (TL)91,121 with Drs. Elizabeth Blackburn and Elissa Epel 
(UCSF) using lymphocytes collected from a subset of caregivers participating in PEPRR (n=20) or TAU (n=20) 
prior to HSCT and three months subsequently. Although caregiver TL did not change between baseline and three 
months after transplant, at baseline TL was negatively related to caregiver burden with a small, albeit significant, 
correlation (r=.31, p=.04, n=40). These observations are provocative and are substantiated by others with regard 
to longer term caregiving.121,129 Telomerase data is not available but we predict it will show changes92 over time 
with regard to reduced caregiver stress associated with our intervention. Lymphocytes will be recovered from 
heparinized whole blood using a standard protocol130 and DNA will be extracted using a Qiagen extraction kit 
(Qiagen DNA blood mini kit Cat No. 51104). A portion of the isolated lymphocytes will be lysed and washed 
through a series of buffers according to kit protocol. The extracted DNA will be suspended, aliquoted into 2-3 O-
ring sealed tubes and stored at -85o C. Lymphocytes and plasma will be stored at -85oC as well. A portion of the 
lymphocytes and DNA will be sent to the Blackburn lab for processing for TL and TA using routine 
procedures.131 This marker is focused on caregivers as it would not be appropriate for patients due to their receipt 
of transplanted cells from a donor.

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Behavioral measures
In the initial RCT, the primary outcome 
measure was the PSS and a number of 
secondary outcomes were further collected 
including measures of depression, anxiety, 
sleep, and overall health.14 We extracted the 
first principal component from four secondary 
measures and PSS by principal component 
analysis (PCA) to produce a composite distress 
score14 which was significantly affected by the 
PEPRR intervention as shown in Figure 5. In 
the present study we have reduced overall 
subject burden by eliminating questionnaires 
with replicative questions so the first principal 
component will be extracted from 3 (rather than 
5) outcomes that had the highest loading for 
caregivers in the PCA of our previous study 
(stress, depression, and anxiety measures 
described below). This composite distress score will be the primary outcome for the caregiver in our conceptual 
model as shown in Figure 3. The main focus for patients is their quality of life so the primary outcome measure 
for patients will be the Functional Assessment of Cancer Treatment – Blood/Marrow Transplant (FACT-BMT).8 
We will collect the same stress, depression, and anxiety measures (specified below) in patients for secondary 
analyses as collected in caregivers.
Demographic survey.  At recruitment each subject will complete a comprehensive demographic survey to 
establish basic facts regarding SES, age, sex, education level, relationship to the patient, caregiving hours, and 
employment status.
Hormone Status. At recruitment, only female subjects will complete a survey regarding their current 
hormone/menopausal status.  
General Health Questions.  This will query health habits (e.g., exercise, nutrition, physician visits) and specific 
medication use.  At each follow up phase we will ask each caregiver as well as patients about changes in 
medication use or the presence of an individual psychotherapist or similar support groups.  
Perceived Stress Scale (PSS). Stress will be assessed with the PSS100 which measures the degree to which 
situations are perceived as stressful. Items on the PSS measure the degree to which the subjects feel their lives 
are unpredictable, uncontrollable and overwhelming on a 5 point Likert scale. It has been validated in 2,387 
respondents across demographic characteristics (i.e. age, sex, SES, race)101 with superior psychometric properties 
(reliability alpha of 0.84). We found PSS to be elevated above controls in caregivers of HSCT patients as well as 
other caregivers of patients in phase 1 trials as indicated in Figure 6. The PSS was the primary outcome measure 
in the initial RCT and was significantly lower than TAU at 3 mo. post-transplant as indicated in Fig. 5. The effect 
size (ES) for this difference was .39.
Center for Epidemiological Studies – depression scale (CES-D). Subjects will complete the CES-D,102 a 
measure developed for the general population and with a long history of use in caregiver research.103-105 The 20 
item scale includes reference to sleep disruption, appetite disturbance, overall fatigue, and depressed affect. 
Scores range from 0-60 with scores over 16 viewed as reflecting significant depressive symptomatology. Test-

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retest validity ranges from .51 to .67 over 2-8 weeks with an internal validity of .85 for a normal population.102 
The ES for the difference in CES-D between TAU and PEPRR was 0.46.
Spielberger State-Trait Anxiety Inventory (STAI). High anxiety been related to caregiver burden and stress.106 
Subject anxiety will be assessed using the State/Trait Anxiety Inventory (STAI).107 The STAI is a 40 item scale 
on which the subjects will indicate how they feel “right now” (state) on a 4 point Likert scale. Internal 
consistency is .89 to .91. The ES for the difference in STAI between TAU and PEPRR was 0.66.
Pittsburgh Sleep Quality Index (PSQI).  The PSQI provides information regarding sleep latency, sleep 
efficiency and sleep duration. The PSQI is a 26 item scale on which the subjects will rate seven domains of 
sleep on a 4 point Likert scale. The PSQI is a widely used questionnaire136 that provides acceptable reliability 
and validity with diagnostic sensitivity of 89.6% and specificity of 86.5%. 137, 138 
FACT-BMT (Patient only). Patient Quality of Life (QOL) follows a time course after allogeneic HSCT9 which 
is characterized by deterioration during hospitalization and as much as one year post-transplant in allogeneic 
HSCT.108 Patients experiencing the greatest improvement in the first year continue to show higher QOL over 
subsequent years109 with female sex being a significant negative contributor to QOL in the patient.108 Thus the 
primary outcome measure for HSCT patient QOL is the FACT-BMT8 which has excellent reliability (.86), 
validity (.89) and sensitivity to change.
Caregiver Reaction Assessment (Caregiver only). We will include a highly recommended28 measure of 
caregiver burden, the Caregiver Reaction Assessment (CRA).110 The 24 item CRA is scored on a 5 point Likert 
scale with subscales of esteem, family support, finances, schedule, and health. It has excellent test-retest 
reliability of .9 and responsiveness to change of .81. We noted that while distress decreased in the PEPRR group, 
the CRA remained similar across groups indicating that the intervention mitigates caregiver distress in spite of 
constant burden. This measure remains as exploratory only.
Carer Support Needs Assessment Tool (Caregiver only). We have included an assessment called Carer 
Support Needs Assessment Tool (CSNAT).135 The instrument is comprehensive in obtaining carers’ 
perspectives of key aspects of support needed during their time as a caregiver for an allogeneic hematopoietic 
stem cell transplant (HSCT).
Caregiver Intervention Feedback (fPER Caregiver only). We have included an assessment called Caregiver 
Intervention Feedback.  We ask very specifically about each component of the intervention.  The questionnaire 
allows caregivers to provide feedback about the intervention earlier than the current 6 month Exit Questionnaire. 
The idea with this addition is that we would provide a forum for participants to comment on the intervention in 
their own words.
Exit Questionnaire.  Each subject will complete the Exit questionnaire at the end of study.  The aim of this 
questionnaire is to get feedback from subjects on our designed intervention program and see what changes 
should be made based of their input. Also for those subjects in the fPER program, we want to get feedback on 
the emWave2 device verses the entrainment and learned behavior of slowed breathing.  This feedback advice 
from subjects will be used in future clinical studies and clinical application.
Adverse Childhood Experiences (Caregiver only). The additional questionnaire will be sent to caregivers after 
they have completed the study. The ACE questionnaire was adapted and used to retrospectively assess forms of 
abuse, neglect, and household dysfunction. ACE will be used to learn more about early childhood experiences 
that may affect your response to the stress of being a caregiver. 

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Digital Videos 
Data will be collected on digital recordings.  The images of individual sessions will be viewed by the co-
investigators to determine the educators’ fidelity to the treatment program as outlined in the manual.  In 
addition, we will ask participants in the fPER program to sign an additional consent for the use of video 
recording from sessions with the lead therapist in order to create a training DVD for new therapists and 
scientific conferences.  
emWave2 
The emWave is a device intended as a tool for stress reduction.  It is not considered a medical device.  The 
emWave has been found to be very safe.  It is intended to be used for educational purposes.
Undiagnosed Psychiatric Condition
There is a risk of diagnosing a pre-existing or underlying mental health disorder that may be discovered as part 
of the subject’s participation in this study.  
E.  Potential Scientific Problems:  
 
A possible problem rests in the burden for the caregiver. We have worked hard to minimize the inconvenience 
to the caregiver in this project to reduce drop outs and maintain compliance. Another issue is related to patient 
death or subject dropout. For this reason, we use intent to treat design with the last valid measure carried 
forward. Subject dropouts will be considered to occur completely at random unless otherwise indicated. 
Caregivers are expected to be generally healthy. It is appreciated that caregiver medications might impact 
biomarkers. Thus medication use will treated as a covariate in the analysis. We appreciate that eliminating 
subjects with illnesses requiring medications would skew the caregivers to only the very healthy and least likely 
to have health impairments associated with caregiving.  Such a strategy would distort the potential impact of the 
intervention on biomarkers and behavior and weaken implications for caregivers in general. It is possible that 
objective caregiver burden might not change as a function of treatment since in many respects the time factors 
and financial burden do not change regardless of the intervention. However it is expected that the subject’s 
perception of how stressful they present themselves (subjective burden) will change and this will be seen in 
affect and stress measures. In summary we remain very excited about this study as it will provide empirical 
evidence regarding the efficacy of the fPER intervention for caregivers of BMT patients.  Further, it will 
provide behavioral and biomarker corroboration regarding the efficacy of fPER.  
Data Safety And Monitoring Plan
Although the risks are considered minimal for this randomized control study, we will create a data safety 
and monitoring board (DSMB) to monitor the progress of the protocol, the safety of the research subjects, and 
data.  The DSMB will consist of two physicians, a social worker, a member of the CAB and biostatistician 
familiar with cancer patients and their families.   None of these individuals will have any direct involvement 
in the proposed project.  The DSMB will meet once a year to evaluate progress to date, the status of all 
subjects unless an adverse event occurs at which time an emergency meeting of the DSMB will be called.  
Drs. Brewer, Kilbourn, Laudenslager and Simoneau will hold monthly study review meetings with the study 
staff involved in the study.  During these meetings, subject recruitment, subject drop-out, individual responses 
to the intervention, and other difficulties encountered in collecting and processing the data or providing the 
treatment interventions will be discussed.  Minutes from these meetings will be kept on file by Dr. 
Laudenslager for future reference as needed.  The PI, other members of the team, and the study biostatistician 
will monitor the data for consistency of collection.  Although this is a treatment study, we do not anticipate 
any severe adverse events to occur associated with the intervention.  In the unlikely event that a subject might 
suffer an adverse event this will be reported to both the DSMB and the Colorado Multi-Institutional Review 

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Board (COMIRB) which oversees the project.  Data will be stored in a database located on a secure password-
protected, HIPAA compliant university server.  
F. Data Analysis Plan:  
Data Aggregation, Distributional Assumptions, Missing Data/Attrition. Data will be screened for errors 
and outliers. Appropriate transformations will be made for non-normal outcomes. The pattern of participant 
dropout will be examined to ensure a reasonably equal distribution of participants lost to follow-up between 
groups. The analytic approach proposed uses maximum likelihood techniques that can include participants 
with incomplete data without need for imputation. These techniques are robust under certain conditions such 
that group comparisons will not be biased as long as missing data is ignorable.132,133 If this is not sufficient to 
minimize influences of particular observations, a sensitivity analysis will be conducted to help determine 
effects of missing data. Separate analyses of only those participants who complete the study will be 
conducted.
Verification of Randomization and Inclusion of Covariates. Preliminary analyses will validate that there are 
no baseline differences between intervention groups. We expect baseline differences will be accounted for by 
randomization, but should differences remain we will co-vary variables that are both correlated with the outcome 
and that differ by group.
Analytic Strategy In general, outcomes will be analyzed with linear mixed models comparing intervention 
(fPER, TAU) in patients and caregivers separately. An alpha level of 0.05 will be used to evaluate significance 
of the a priori planned comparisons. Two-tailed tests are proposed in order to detect differences between fPER 
and TAU in either direction. The software SAS PROC MIXED will be used.134 The analytic aims and hypotheses 
are briefly stated, followed by overall analytic plan for primary and secondary outcomes:
Aim 2: Assess patient QOL following an allogeneic HSCT by the FACT-BMT as the primary patient 
outcome. Patients whose caregivers receive fPER will have improvements in FACT-BMT compared to 
TAU.
Aim 3: Test impact of fPER on caregiver composite distress score of depression, anxiety, and stress as the 
primary caregiver outcome. Caregivers who receive fPER will have reduced distress compared to TAU.
For hypotheses addressing group differences for patients and separately for caregivers, outcomes will be 
evaluated with the same design: 2 groups (fPER, TAU) at 2 clinics (CBCI, UCH) over 4 times (prior to 
transplant, 6 wks., 3 mo., 6 mo.). Mixed models will specify group, clinic, time, and their interactions as 
fixed effects and subject as a random effect, where subject is assumed independently normally distributed 
with mean 0 and variance independent of the random errors. The primary caregiver model of composite 
distress will include caregiver age as a covariate because it related to caregiver distress in our prior study11; 
secondarily, we will investigate inclusion of patient FACT-BMT as a covariate. The primary patient model of 
FACT-BMT will include no covariates, but secondarily will explore inclusion of caregiver distress as a 
covariate.
Aim 4: Assess biomarkers of allostatic load in patients prior to transplant and caregivers during the 
transplant process using novel biomarkers. Patient’s hair cortisol will predict their QOL and distress at the 
beginning of the transplant process. fPER will be associated with reduced allostatic load in caregivers who 
receive fPER compared to those receiving TAU.

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Linear mixed models will similarly be used to evaluate group differences in these biomarkers separately in 
patients and caregivers. Caregiver age and patient FACT-BMT will be evaluated for inclusion in caregiver 
models. Caregiver composite distress score will be evaluated for inclusion as a covariate in patient models.
Subject sample size and power analysis.  Our prior 
trial demonstrated medium effect sizes (0.39-0.45) 
for PEPRR in caregivers. We believe the proposed 
modifications in fPER will likely increase its effect 
for caregivers. However, the effect of fPER on 
patient QOL is indirect, and thus smaller effect sizes would be expected. We estimated minimum effect sizes 
detectable for different power specifications for a recruited sample size of 112 per treatment group and also for 
smaller sample sizes, allowing for increased variability due to estimated losses to follow-up of 34% at 3 mo., and 
45% at 6 mo. based on our prior caregiver trial. Estimates are conservative since fPER has been specifically 
modified to reduce attrition. 112 dyads (consisting of a caregiver and patient) randomized to each group provide 
excellent power (>95%) for detecting the medium effect size expected for the composite distress score in 
caregivers and are necessary to provide adequate power (80-85%) for detecting smaller effect sizes expected for 
the FACT-BMT QOL measure in patients. Estimates are also conservative because mixed model analyses that 
include all subjects (even those with only a single observation) have been shown to provide the greatest power.127
G. Summarize Knowledge to be Gained:  
This study will provide empirical evidence regarding both behavioral and possible physiological efficacy 
of a stress management psychoeducation program for caregivers and the impact on patient QOL.  This is one of 
the few studies of its kind that promises to provide not only information regarding behavioral outcome for the 
patients as far as quality of life but also impact their caregivers. The results of this study will lead to the 
availability of a manual developed for this intervention that can be disseminated to other HSCT programs 
leading to improved patient QOL and reduced caregiver distress.
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