Preliminary Evaluation of an Internet-Assisted Cognitive Behavioral Intervention for Targeted Therapy Fatigue
Phase: NA
Conditions: Chronic Myelogenous Leukemia
Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Preliminary Evaluation of an Internet-Assisted Cognitive Behavioral Intervention 
for Targeted Therapy Fatigue 
NCT02592447 
Version 7 
December 7, 2016 

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A. SPECIFIC AIMS 
 
Targeted therapies are a new generation of cancer drugs designed to interfere with molecular targets critical 
for tumor growth and progression. One of the first and most successful examples is the oral medication 
imatinib (Gleevec®), a tyrosine kinase inhibitor (TKI) developed for chronic myelogenous leukemia (CML). 
Following its introduction, 8-year survival rates for CML improved from <20% to >85%. Several second-
generation TKIs have since been approved for CML, and other oral medications targeting TKI pathways have 
been or are being developed for many other forms of cancer. Although imatinib and similar TKIs are much 
better tolerated than the regimens they replaced, these medications do possess side effects that are 
bothersome to patients, interfere with quality of life (QoL), and contribute to problems with adherence. Since 
TKI therapy typically continues on a daily basis for many years and may be life-long, effective management of 
side effects is critically important. Research consistently shows that fatigue is the most common symptom in 
CML patients taking TKIs and the main factor adversely affecting their QoL. It is highly surprising then that 
there are no published trials of interventions addressing targeted therapy-related fatigue (TTF). 
 
Research has shown cognitive behavior therapy (CBT) is effective against fatigue in disease-free cancer 
survivors who have completed treatment. Based on this evidence, CBT was among the interventions 
recommended in guidelines recently developed by the American Society of Clinical Oncology (ASCO) for 
addressing fatigue in clinically disease-free cancer survivors, including CML patients on maintenance TKI 
therapy. CBT for Post-Cancer Fatigue (CBT-PCF), an intervention developed by the Consultants in the 
Netherlands, was specifically cited as an example of an effective strategy based on a randomized trial showing 
it produced clinically significant improvements maintained over an extended period of time in disease-free 
cancer survivors who were initially experiencing heightened fatigue following treatment completion.     
 
We propose to build on CBT-PCF, with assistance from its developers, to create a new Internet-assisted form 
of CBT to address TTF (CBT-TTF). CBT-PCF’s conceptual basis is the precipitating-perpetuating model of 
symptom evolution. Research shows that, once a cancer treatment (e.g., chemotherapy) has precipitated 
fatigue, certain cognitive and behavioral responses (e.g., catastrophizing and reduced physical activity) then 
perpetuate it in the posttreatment period. Consistent with this model, CBT-PCF has been delivered in-person in 
clinic settings using a tailored approach in which up to 6 modules are administered to address perpetuating 
factors assessed as operative. Unlike chemotherapy patients, CML patients continue to take a medication that 
can precipitate fatigue. However, research shows that many of the same factors that perpetuate fatigue in the 
posttreatment period also serve to exacerbate it while patients are on treatment.   
 
Accordingly, the first step is to adapt CBT-PCF, an intervention based on the precipitating-perpetuating model 
and designed for fatigued cancer patients who completed treatment, to develop CBT-TTF, an intervention 
based on a revised precipitating-exacerbating model and designed for fatigued patients on maintenance oral 
targeted therapy. Adopting the tailored modular approach, the team recently completed qualitative research 
with fatigued CML patients on maintenance TKIs and CML care providers to determine which CBT-PCF 
modules to retain and adapt and to identify potential new modules to develop based on the conceptual model. 
In addition, the team has completed formatting the intervention for real-time face-to-face videotelephony 
delivery via 4G equipped computer tablets (FaceTime via iPads) to minimize travel burden and maximize 
convenience for participants and to enhance dissemination potential. Now that initial development work has 
been completed, we propose to evaluate CBT-TTF with fatigued CML patients on TKIs for feasibility, 
acceptability and potential efficacy relative to usual care only in a small-scale randomized controlled trial.   
 
The specific aims of this protocol are to: 1) Evaluate CBT-TTF and related methods for feasibility and 
acceptability; 2) Explore the efficacy of CBT-TTF in reducing fatigue (primary outcome); 3) Explore the 
efficacy of CBT-TTF in improving quality of life and oral medication adherence (secondary outcomes); 
and 4) Explore the efficacy of CBT-TTF in modifying factors identified as intervention targets (tertiary 
outcomes). 
 
 
 

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B. BACKGROUND 
B.1. Advent of Targeted Cancer Therapies. Targeted therapies are a new generation of drugs designed to 
interfere with molecular targets that play a critical role in tumor growth and progression. One of the first and 
most successful examples was in treatment of chronic myelogenous leukemia (CML). With ~5000 cases 
diagnosed annually in the U.S.1, CML accounts for 20% of new adult leukemias. Based on research showing 
the cause to be formation of the BCR-ABL oncogene that produces a constitutively active tyrosine kinase
2, the 
oral medication imatinib (Gleevec®) was evaluated because it is a potent inhibitor of this enzyme3. Clinical 
trials confirmed its efficacy
4,5 and demonstrated clinically significant differences in quality of life (QoL) favoring 
imatinib
6 over the existing regimen.  Eight-year survival rates for CML patients have since improved from <20% 
historically to 87% in the imatinib era7. The success of imatinib is widely considered a model for development 
of other targeted cancer therapies8. Several second-generation tyrosine kinase inhibitors (TKIs) have since 
been approved for use against CML8 and other oral medications targeting tyrosine kinase pathways have been 
or are being developed for many other forms of cancer9.   
 
B.2. Fatigue Reports in CML Patients Prescribed TKIs. Due to high potential for recurrence
10-12, daily use of 
TKIs in CML typically continues for many years and may be life-long.  This situation necessitates effective 
management of TKI side effects.  Although imatinib and similar TKIs are better tolerated than many regimens 
they replaced
6, evidence suggests they possess bothersome side effects that interfere with QoL and contribute 
to nonadherence
13-16. Moreover, several studies indicate fatigue is the most problematic symptom experienced 
by CML patients. Efficace et al13 found that among 422 CML patients on imatinib an average of 5 years and 
assessed with a 9-item TKI-specific checklist, fatigue was most common; it was present in 82% of patients and 
rated as “quite a bit” or “very much” bothersome by 29%. Williams et al
17 found that among 152 CML patients 
(93% on TKIs) who rated 20 symptoms (0-10) with the MDASI-CML
17, fatigue had the highest severity rating 
(M=2.67) and the highest percentage of moderate-severe (>5) ratings (21%). Differences among TKIs were not 
significant. Efficace et al18 asked 236 CML patients on TKIs and 59 CML care providers to identify from among 
74 QoL issues  a “top 10” list; fatigue was most frequently nominated by each group. Another report speaks to 
clinical significance. Efficace et al19 evaluated the relationship of symptoms, clinical features, and 
demographics to QoL (SF-3620).  Fatigue (FACIT-F
21) was independently associated with worse QoL on all  
SF-36 scales (p<.05) and had the highest inclusion frequency of all variables examined. The presence of 
fatigue was also associated with greater symptom burden, a factor related to poorer TKI adherence in CML 
patients16. These findings led the authors to conclude, “… fatigue is the main factor limiting the [health-related] 
QOL of CML patients who receive long-term imatinib therapy”
19. 
 
B.3. Interventions to Address Targeted Therapy-Related Fatigue (TTF).  Despite its importance, we could 
not identify any published intervention trials for TTF. In the absence of understanding TTF’s pathophysiology19, 
recently issued clinical practice guidelines for addressing fatigue in cancer survivors
22 suggest promising 
strategies. The guidelines state they are applicable to patients off-therapy as well as patients on maintenance 
therapies such as TKIs for CML
22. While evidence was insufficient to recommend pharmacologic therapies, it 
was sufficient to recommend physical activity interventions and cognitive behavior therapy (CBT). With regard 
to the latter, an intervention developed by the Consultants was cited as a prime example
23. This intervention 
(CBT for Post-Cancer Fatigue or CBT-PCF) was designed for disease-free patients who completed treatment 
but were experiencing elevated fatigue. Its conceptual basis, the precipitating-perpetuating symptom model, 
has been applied successfully to chronic pain and sleep problems24,25. We have shown the model to be 
applicable to cancer-related fatigue in that treatments (e.g., chemotherapy) routinely function as precipitating 
factors, while certain cognitive responses (e.g., catastrophizing) and behavioral responses (e.g., reduced 
physical activity) to fatigue contribute to its persistence and worsening over time26,27. Based on this model and 
relevant research, CBT-PCF focuses on 6 possible perpetuating factors: insufficient coping with cancer; fear of 
disease recurrence; dysfunctional fatigue-related cognitions; sleep dysregulation; activity dysregulation; and 
low social support/negative social interactions. An innovative feature is use of a modular approach in which the 
intervention is tailored based on those perpetuating factors assessed as operative. To test it, 112 fatigued 
cancer survivors in the Netherlands were randomized to CBT-PCF or a wait-list control condition
23.  The 
intervention (M=12.5 1-hour sessions) was delivered in-person in clinic settings by trained and supervised 
therapists.  Fatigue (primary outcome) was assessed at baseline and 6 months later using the CIS
28. At 6 
months, CBT-PCF patients showed a greater decrease in fatigue than control patients (p<.001); clinically 

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significant improvement (based on reliable change index) was evident in 54% of CBT-PCF patients vs. 4% of 
control patients (p<.001)23.  At a follow-up a median of 2 years after therapy completion, fatigue remained 
lower than at baseline (p<.05) and similar to levels seen at the 6-month assessment among patients offered 
CBT-PCF29. 
 
B.4.  Adaptation  of  CBT-PCF. As noted earlier, the team recently completed the process of adapting CBT-
PCF for use with fatigued patients on maintenance oral targeted therapy. This work, which was accomplished 
under another IRB-approved protocol, involved conducting in-depth interviews with 10 CML patients at Moffitt 
prescribed a TKI who were experiencing heightened fatigue and 4 health care professionals at Moffitt (two 
MDs, two ARNPs) who provide care to patients with CML.  In general, patients and providers felt that all the 
existing modules were relevant and had potential to improve fatigue in patients on maintenance oral targeted 
therapy.  Suggested changes focused on modifying reference to fear of cancer recurrence (an issue more 
relevant to patients who have completed treatment for early stage solid tumors) to instead refer to fear of 
increasing disease activity (an issue more relevant to patients who are on maintenance therapy to control their 
disease). Interviews also suggested that patients would benefit from psychoeducation designed to review 
understanding of their disease and its treatment, provide basic factual information their disease and its 
treatment, and identify discrepant beliefs about their disease and treatment that could be addressed as part of 
other modules (e.g., the helpful thinking module). Based on feedback, a number of minor changes were made 
to the therapy manual and an additional psychoeducation module was created. Finally, feedback about the 
proposed delivery channel for the intervention (i.e., FaceTime using iPads) from patients and providers was 
generally positive. 
 
C. APPROACH 
C.1.  Approach  Overview. A pilot RCT will be conducted in which fatigued CML patients taking TKIs are 
randomized to a CBT-TTF intervention condition (CBT-TTF) or a wait-list control condition (WLC).  As part of 
trial initiation, we will seek to recruit and obtained informed consent for up  to 3 patients per treating therapist 
and provide them with CBT-TTF and administer all study measures so the therapists can gain experience in 
administering the intervention per protocol before they are assigned patients randomized to receive the 
intervention. Data for these patients will not be included with data based on randomization of study 
participants. As noted below, therapists will have already studied the intervention and practiced it before this 
activity takes place and will be closely supervised by senior clinicians with considerable relevant experience.  
 
C.2.  Eligibility  Criteria. Participants must: 1) be >18 years old; 2) be able to speak/read English; 3) be 
diagnosed with chronic phase CML; 4) not have been treated for other cancer (except non-melanoma skin 
cancer) in the past 5 years; 5) be under the care of a MCC physician; 6) be on the same oral TKI for >3 
months; 7) new onset or worsening of fatigue since starting TKI; 8) report moderate-severe fatigue in past 
week (FSI average rating >4 of 0-10)30; and 9) have no clinical history of disease (e.g., multiple sclerosis, 
fibromyalgia) that could account for their fatigue presentation. Patients must not: 1) be scheduled to 
discontinue their TKI under medical supervision within the next 3 months.  
 
C.3. Recruitment. Participants will be identified via review of medical records compliant with HIPAA guidelines 
or through the cancer registry. Those identified will be telephoned by the Study Coordinator (SC), at which time 
the study will be described and they will be screened for fatigue (eligibility criteria #7-8 above). Those who 
meet all eligibility criteria and express interest in participating will be sent a secure email link to an online 
informed consent form (if they have Internet access) or will be mailed a paper copy of an IRB-approved 
consent form along with a  postage-paid return envelope (if they do not have Internet access) to review. The 
SC will re-contact the patient by telephone to see if he/she has any questions and to see if he/she wishes to 
participate.  
C.4. Baseline Assessment. Those patients providing informed consent will be asked to complete a baseline 
(T1) questionnaire using a secure weblink (if they have Internet access) or a scanable form mailed to them 
along with a postage-paid return envelope (if they do not have Internet access). See below for content of this 
40-minute questionnaire. The Study Coordinator (SC) will be available via a toll-free telephone number to 

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answer any questions and provide any needed assistance. Participants will be paid $25 for completing this 
assessment. 
 
C.5.  Randomization. A randomization schedule will be prepared by the MCC Biostatistics Core under Dr. 
Small’s supervision and transferred to a secure intranet application. As noted below (C.10.5), participants will 
be randomized to CBT-TTF or WLC on a 2:1 basis. Randomization will be stratified by gender.  After 
completion of the baseline questionnaire, the SC will use it to assign patients in a 2:1 ratio  to CBT-TTF or 
WLC. The SC with then notify the participant by telephone of his/her intervention assignment and describe next 
steps based on intervention assignment (see C.6 and C.7).  
 
C.6.  Wait-List  Control  Condition  (WLC). Participants randomized to this condition will continue to receive 
care under direction of their MCC physician. Physicians will be informed by email of patients’ participation on 
the basis of elevated fatigue and their randomization to WLC.  Chart review and a patient self-report form will 
be used at baseline and follow-up assessments to determine what, if any, services or interventions participants 
received in the preceding 18 weeks that might address fatigue.  Similar data will be collected for CBT 
participants for services and interventions unrelated to study participation. Upon completion of the follow-up 
assessment (see below), participants randomized to WLC will be offered the opportunity to receive CBT is the 
same manner as described below (see. C.7). Follow-up questionnaire data will be collected from WLC 
participants who elect to receive CBT as described in Tables 1 and 2.  
 
C.7. Cognitive Behavior Therapy for Targeted Therapy-related Fatigue (CBT-TTF) 
C.7.1. Content and Delivery. CBT-TTF retain CBT-PCF’s basic format of assessing perpetuating/exacerbating 
factors and selecting modules based primarily on factors determined to be operative
23.  The assessment of 
these factors will occur as part of the baseline assessment.  See below for details on assessment of these 
factors. Consistent with CBT-PCF, therapists will introduce the intervention and its rationale in an initial in-
person session held at Moffitt. The therapist will also present results of the assessment of 
perpetuating/exacerbating factors during this session and will outline the therapy plan based on the modular 
approach. This initial session is expected to last 90 minutes. Determination of the ordering of modules will be 
decided during therapist supervision (see below). Each CBT-TTF module (with the exception of 
psychoeducation) follows a basic format of problem recognition, solution generation, implementation, and 
progress evaluation. Subsequent sessions will initially be held weekly for approximately 45 minutes each using 
FaceTime (see below) at a time mutually agreed upon by the participant and therapist. Depending on 
participant progress in meeting therapy goals, therapists will have the option of scheduling some sessions at 1- 
2- or 3-week intervals.  As with CBT-PCF, participants who completed all planned therapy sessions prior to 
week 18 will receive one or more booster sessions at 1-, 2- or 3-week intervals. These booster sessions are 
designed to monitor participant’s continued used of recommended strategies to address fatigue.  As with CBT-
PCF, a final session will summarize progress and ways to maintain therapeutic gains. Participants will be given 
the option of conducting this final session in-person at Moffitt or via FaceTime.   A complete description of 
CBT-TTF is provided in the Therapy Manual included as an Appendix.  
C.7.2. Therapist Training and Supervision. Therapists are students admitted to the USF Clinical Psychology 
Doctoral Program. As part of their study-related activities, therapists will participate in training, supervision, and 
treatment fidelity oversight as described below. Dr. Jim, licensed psychologist with considerable experience in 
providing CBT, has already trained two therapists in collaboration with the Consultants (Drs. Knoop and 
Gielissen), developers of CBT-PCF. Training involves the therapists reviewing the CBT-TTF therapy manual 
and then rehearing intervention elements in modeling and role-playing sessions. As part of this protocol, each 
therapist will be assigned up to 3 patients who meet all eligibility criteria and provide informed consent in order 
to gain experience delivering the intervention per protocol before they are assigned participants on the basis of 
randomization.  Throughout the time they provide interventions to participants, the therapists will meet weekly 
with Dr. Jim for supervision.  Dr. Jim will use audio recordings of therapy sessions and therapist observations 
to ensure CBT-TTF is administered effectively and consistent with the manual. Dr. Knoop will participate in the 
supervision sessions via videconference during initial months of each therapist’s activity to address any new 
issues that may not have arisen during training.   
C.7.3. Intervention Fidelity.  Audio recordings will be made of all therapy sessions; 25% of each therapist’s 
sessions will be selected randomly on an ongoing basis for fidelity rating.  Using checklists specific to each 

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module, Dr. Jim will rate adherence to key intervention elements and describe instances of nonadherence. 
This information will be shared with the therapist and Dr. Jim and used in supervision sessions to promote 
continued fidelity. It will also be summarized for reporting purposes. 
C.7.4. Use of Videotelephony. Following the initial in-person session, CBT-TTF will be delivered in real time 
and face-to-face via an encrypted videotelephony application (FaceTime) using iPads (Model A1454), an 
approach  that  meets  HHS  standards  for  security  and  privacy  and  is  HIPAA  compliant  
(healthit.gov/mobiledevices). The rationale for this approach over in-person clinic-delivered sessions is to 
minimize travel burden, maximize convenience, and foster greater dissemination potential, while maintaining 
key elements of face-to-face therapeutic interactivity.  iPads programmed and modified by the MCC Survey 
Methods Core will be 4G equipped so individuals without Internet access can participate and for security 
purposes. Each device will be WPA-2 password enabled and loaned to a participant for the duration of 
participation. Restrictions will be set to protect iPads from virus contamination, including not allowing Wi-Fi 
access since many networks are not encrypted or password secured.  As part of intervention assignment 
notification, the SC will demonstrate iPad use, place a practice FaceTime call to the participant, and arrange 
regular and convenient times for FaceTime sessions. Participants will also be provided with the name and 
telephone number of a contact in the MCC Survey Methods Core who can provide any needed technical 
assistance.  
 
C.8. Follow-up Assessments.  Based on the once weekly format, we estimated that the maximum number of 
modules can be completed within 18 weeks. Accordingly, all participants will be asked to complete the follow-
up (T2) questionnaire approximately 19 weeks post randomization (see below for content). Participants will be 
asked to complete the form online using a secure weblink (if they have Internet access) or on paper using a 
form mailed to them by the SC along with a postage-paid return envelope.  The SC will telephone and or email 
participants to remind them to complete the form up to 3 times if it is not completed and returned within 5 
business days of being made available to participants.  Waitlist control participants who elect to receive the 
intervention will complete a T3 questionnaire after they complete the intervention.  The T3 questionnaire will be 
identical to the T2 questionnaire.  Participants will be paid $25 for completing each follow-up questionnaire.  
 
C.9. Study Measures. 
C.9.1. Demographic and Clinical Characteristics. Demographic information (e.g., age, gender, race, ethnicity, 
marital status, education, occupation, income, alcohol use, tobacco use, prescription and non-prescription 
medication use, history of fatigue and self-reported comorbidities31 will be collected via a self-report form at T1. 
Clinical information (e.g., height, weight, Sokal group, CML diagnosis date, current TKI start date, dosing 
instructions for current TKI, previous TKI [if applicable], current additional targeted therapy [if applicable], 
current hematologic response [complete, incomplete, none], date of current hematologic response, current 
cytogenetic response [complete, partial, minor, minimal, none], date of current cytogenetic response, current 
molecular response [complete, major, none), and date of current molecular response] will be collected via chart 
review at T1 and T2.  
C.9.2. Primary and Secondary Outcomes. The primary outcome (fatigue) and secondary outcomes (QoL, 
adherence) outcomes will be assessed via self-report at T1 and T2 (see Table 1). CBT-TTF participants will 
also be asked at follow-up to rate their satisfaction with the intervention using items used previously to evaluate 
Internet-assisted interventions.
32 
Table 1. Primary and Secondary Outcomes and Associated Measures 
Fatigue will be assessed with the Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-
Fatigue)21 v.4, a 13-item self-report measure yielding total score with demonstrated reliability, validity, 
sensitivity to change21 and an identified Minimally Clinically Important Difference (MID)
33 
Quality of life will be assessed with the Functional Assessment of Cancer Therapy General Scale (FACT-
G)34 v.4, a 27-item measure yielding  total score and scores for physical, social/family, emotional, and 
functional well-being of demonstrated reliability, validity, and sensitivity to change
34 
 Medication adherence will be assessed with the self-report Morisky Medication Adherence Scale (MMAS), 
an 8-item self-report measure of demonstrated reliability and validity35 used previously with CML patients
36  
Symptom burden and impact on daily functioning will be assessed with the M.D. Anderson Symptom 
Inventory for Chronic Myelogenous Leukemia  (MDASI-CML)
17, a 26-item self-report measure yielding total 

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C.9.3. Perpetuating/Exacerbating Factors. As described above, CBT-TTF participants will be assessed for 
perpetuating/exacerbating factors at T1 in order to determine the selection of certain therapy modules. They 
will be reassessed for the same factors at T2.  WLC participants will also be assessed on these factors at T1 
and T2. These data will be used to explore whether intervention assignment was related to changes on factors 
identified as therapeutic targets. See Table 2 for descriptions of factors to be assessed and measures to be 
used to assess those factors. Please note that for some factors there is more than one measure to be used for 
assessment purposes. Should scores on any measure for a factor exceed the cut-off, that measure will be 
included in CBT-TTF. All CBT-TTF participants will receive the Psychoeducation module; therefore, there is no 
measure associated with this module.    
score with demonstrated reliability, validity, and sensitivity to change. 
Table 2. Perpetuating/Exacerbating Factors (Tertiary Outcomes and Associated Measures 
The Sickness Impact Profile (SIP) sleep-rest subscale is a 7-item measure assessing sleep-rest 
patterns.37,38 Respondents are asked to check a box next to the symptoms that apply to them. Higher scores 
are indicative of more dysregulated sleep-rest patterns. Based on previous research,23 a cutoff of ≥60 will be 
used to determine whether participants should receive the Disturbed Sleep/Wake Rhythm module of CBT-
TTF. 
The Daily Sleep Diary is an 8-item assessment of sleep-wake patterns administered daily.39 Daily ratings are 
averaged together to yield a total score with higher scores indicating poorer sleep. An average weekly rating 
of 5 or higher will be used to indicate poor sleep and to determine whether participants should receive the 
Disturbed Sleep/Wake Rhythm module of CBT-TTB.  
The Checklist for Individual Strength (CIS) is a 20-item measure that assesses subjective fatigue and related 
behavioral components of fatigue.28 This study will focus on the concentration scale which is a 5-item 
measure that assesses the extent to which patients are experiencing concentration problems in the last two 
weeks. Each item is rated on a 7-point response scale ranging from “yes, this is true” to “no, that is not true”. 
Concentration scores can range from 5 to 35 with higher scores indicating more concentration problems. A 
cutoff of 16 will be used based on prior research23 to determine whether participants should receive the 
Activity Regulation module of CBT-TTF. 
The Sickness Impact Profile (SIP) social interaction subscale is a 20-item measure that assesses negative 
social interactions.37,38 Respondents are asked to check a box next to the items that apply to them. Higher 
scores are indicative of more dysfunctional social interactions. A cutoff of 150 will be used based on prior 
research
23 to determine whether participants should receive the Activity Regulation module of CBT-TTF.  
The International Physical Activity Questionnaire (IPAQ) Short Form is a 7-item measure assessing health-
related physical activity.
40  Items are assessed in 4 generic domains including moderate and vigorous 
physical activity, walking, and sitting. Respondents are asked to rate how many days per week they engage 
in the activity and for how much time per day. Physical activity is then classified into low, moderate, or high 
levels with higher classifications indicating greater activity. American Cancer Society guidelines41 
recommend 150 minutes of moderate intensity activity or 75 minutes of vigorous intensity activity each week 
(or a combination of these).  These guidelines will be applied to IPAQ reports and participants who do not 
meet this threshold will be administered the Activity Regulation module of CBT-TTF. 
The Impact of Events Scale (IES) is a 15-item measure assessing psychological stress.42 Both the intrusion 
and avoidance subscales of the IES will be used for this study. Items are rated on a 4-point response scale 
(0=no bother/avoidance; 3=often bothered/avoids). Based on prior research,
23 scores of 10 or above are 
indicative of significant psychological stress and will be used to determine whether participants should 
receive the Insufficient Processing module of CBT-TTF. 
The Illness Cognition Questionnaire (ICQ) is an 18-item measure that assesses favorable and unfavorable 
ways of adjusting to chronic illness.43 Each item is rated on a 4-point response scale (1=does not agree at 
all; 4=completely agrees). The ICQ groups cognitions into three dimensions including acceptance, 
helplessness, and perceived benefit. This study will focus on acceptance for which a cutoff of ≤12 will be 
used and helplessness for which a cutoff of >14 will be used based on prior research23 to determine whether 
participants should receive the Dysfunctional Thinking module of CBT-TTF.  
The Self-Efficacy Scale 28-Fatigue (SES28) is a 5-item measure assessing the extent to which a respondent 
feels they have control over their fatigue.
44 Items are rated on a 5-point scale ranging from “no, out of the 

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C.10. Statistical Analyses. 
C.10.1. Preliminary Analyses. Descriptive and graphical statistics will be used to check distributional 
assumptions and appropriate transformations or non-parametric methods will be applied as necessary. 
Analyses will be conducted to evaluate if randomization was successful in yielding groups equivalent with 
regard to demographic and clinical characteristics. If even marginally significant differences (p<.1) are 
observed, the characteristic will be included as a covariate in subsequent multivariable analyses.  
C.10.2. Analyses Related to Aim 1. To calculate the participation rate, the number of individuals who consent 
will be divided by the number of individuals who meet all eligibility criteria and provide an informed consent. 
The study will be considered acceptable if this rate is >50%. To calculate the retention rate, the number of 
individuals who complete baseline and follow-up assessments will be divided by the number of individuals who 
provide informed consent and are not discontinued due to ineligibility. To calculate the CBT-TTF completion 
rate, the number of sessions participants in this condition are expected to complete will be divided by the 
number of classes actually completed.  The study will be feasible if these two rates are >70%.    
C.10.3. Analyses Related to Aims 2, 3 and 4. FACIT-F scores at baseline and follow-up (primary outcome) will 
be treated two ways. First, they will be used as continuous variables in a repeated measures analysis (SAS 
PROC MIXED) to evaluate longitudinal changes as a function of group assignment (CBT-TTF vs. UCO). 
Although data will be evaluated for statistical significance, the primary purpose is to compute the effect size 
(Cohen’s d) at follow-up (i.e., difference between the groups divided by pooled standard deviation). CBT-TTF 
will be considered potentially efficacious if d>0.5 (i.e., medium sized effect) favoring CBT-TTF. A similar 
strategy will be applied to continuous FACT-G and MARS scores (secondary outcomes) and scores for 
question” to “yes, I’m sure”. Higher scores are indicative of a greater sense of control over fatigue 
symptoms. Based on previous research,23 a cutoff of <19 will be used to indicate low self-efficacy in this 
study and to determine whether participants will receive the Dysfunctional Thinking module of CBT-TTF. 
The Fatigue Catastrophizing Scale (FCS), a 10-item measure that assesses catastrophizing thoughts about 
fatigue.
27 Each item is rated on a 5-point response scale ranging from “never true” to “all of the time true”. A 
total score is derived by averaging the 10 ratings. Higher scores on the FCS are indicative of greater 
catastrophizing thoughts. A cutoff of ≥16 will be used based on prior research23 to indicate whether or not a 
patient is having catastrophizing thoughts about their fatigue and to determine whether participants should 
receive the Dysfunctional Thinking module of CBT-TTF. 
The Illness Management Questionnaire-Focusing on Symptoms (IMQ--factor III) is a 9-item subscale of the 
Illness Management Questionnaire that assesses the extent to which patients are preoccupied by their 
symptoms and appraise their life as dominated by their symptoms.45 Items are rated on a 6-point response 
scale ranging from “never” to “always.” Higher scores are indicative of greater preoccupation with symptoms. 
Based on previous research,23 a cutoff of ≥10 will be used in this study to determine whether patients should 
receive the Dysfunctional Thinking module of CBT-TTF 
The Social Support List-Negative Interactions (SSL-N) is a 14-item measure that assesses perceptions of 
negative social interactions.  The SSL was developed in the Netherlands and was validated with an English-
language sample.
46 Items are rated on a 4-point scale ranging from “seldom or never” to “very often” with 
higher scores indicating that the respondent experiences more negative interactions. Based on prior 
research,
23 a cutoff of ≥10 will be used to determine whether participants should receive the Social Support 
and Interactions module of CBT-TTF. 
The Social Support List-Discrepancy (SSL-D) is a 8-item measure that assesses discrepancy between 
perceived and desired social support. The SSL was developed in the Netherlands and was validated with an 
English-language sample.46 Items are rated on a 4-point scale ranging from “I miss it, I would like it to 
happen more often” to “It happens too often, it would be nice if it happened less often”. Higher scores are 
indicative of a greater discrepancy between perceived and desired social support. Based on prior research,
23 
a cutoff of ≥53 will be used to determine whether participants should receive the Social Support and 
Interactions module of CBT-TTF. 
The Cancer Worry Scale (CWS), an 8-item measure that assesses concerns about developing cancer or 
experiencing a cancer recurrence47 has been adapted for use in the current study. Each item is rated on a 4-
point response scale (1=“never”; 4=“almost always”). Higher scores indicate that the respondent 
experiences more frequent worries about their cancer.  A cutoff of >1447 will be used to determine whether 
participants should receive the Heightened Fear of Increase in Disease Activity module of CBT-TTF. 

9 
 
measures of perpetuating/exacerbating factors (tertiary outcomes). Second, we will classify each participant’s 
change on the FACIT-F for whether or not it meets a minimal clinically important difference of  >3 points of 
positive change33. This dichotomous score will then be used as the outcome in a logistic regression analysis 
with intervention group as the predictor.  Finally, we will conduct exploratory analyses to evaluate if the number 
of sessions of CBT-TTF moderates changes in FACIT-F scores using a residualized change regression 
approach. 
C.10.4. Missing Data and Protection of Type I Error.  Multiple imputation will be used for sporadic missing 
data48. To protect against Type I error, principal analyses for Aims 2-3 are designed to answer well-defined 
questions about potential efficacy based on well-specified primary and secondary outcome variables. All tests 
will be two-tailed at alpha=.05. 
C.10.5. Sample Size. Because this is an exploratory study, we seek a sample size that will provide reliable 
estimates of feasibility and acceptability. Accordingly, we will enroll 48 participants allocated on a 2:1 ratio to 
the intervention arm (n=32) and the control (n=16).  Nevertheless, these sample sizes allow us to detect 
between group differences of .88 SD units at follow-up with power=.80 at alpha=.05 (two-tailed), a difference 
smaller than that observed by Gielissen et al.23 for CBT-PCF at the 6-month point (d = 1.04). Moreover, the 
within group sample sizes used here allow us to detect a change of .51 SD units, which corresponds to the 
threshold for potential efficacy described above. Pharmacy data indicate MCC physicians care for ~370 CML 
patients on TKIs. If only 40% are eligibility criteria and agree to participate (n=148), numbers are still sufficient 
to complete the proposed work. 
 
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