Stepped-Care Telehealth for Distress in Cancer Survivors
Phase: NA
Conditions: Anxiety, Depressive Symptoms, Sleep Disturbance, Recurrent Disease, Fatigue, Quality of Life, Cancer
Sponsor: Wake Forest University Health Sciences

 
 
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COVER PAGE 
 
DCP Protocol #: WF-30917CD 
 
Local Protocol #: WF-30917CD 
 
A STEPPED-CARE TELEHEALTH APPROACH TO TREAT DISTRESS IN 
CANCER SURVIVORS 
 
Consortium Name: 
 
 
Wake Forest NCORP Research Base  
Name of Consortium Multi- 
 
Glenn Lesser, MD 
Principal Investigator 
 
Department of Internal Medicine 
 
 
Section on Hematology and Oncology 
 
 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC  27157 
Telephone: (336) 716-0891 
Fax: (336) 716-6275 
E-mail address: glesser@wakehealth.edu  
 
Consortium Name: 
 
 
Wake Forest NCORP Research Base 
Name of Consortium Multi- 
 
Kathryn Weaver, PhD, MPH 
Principal Investigator  
 
Associate Professor of Public Health Sciences 
 
 
 
 
 
Department of Social Sciences & Health Policy 
 
 
 
 
 
Medical Center Boulevard 
 
 
 
 
 
Winston-Salem, NC 27157 
 
 
 
 
 
Telephone: (336)713-5062 
 
 
 
 
 
Fax: (336) 716-7554 
 
 
 
 
 
E-mail address: keweaver@wakehealth.edu 
 
Organization Name: 
 
 
Wake Forest School of Medicine  
Protocol Principal Investigator: 
Suzanne C. Danhauer, PhD 
 
 
Department of Social Sciences & Health Policy  
 
 
Division of Public Health Sciences 
 
 
Medical Center Boulevard 
 
 
Winston-Salem, NC 27157 
                                                           Telephone: (336) 716-7402  
 
 
Fax: (336) 716-7554 
 
 
E-mail address: danhauer@wakehealth.edu  
 
Organization Name: 
 
 
Wake Forest School of Medicine  
Protocol Principal Investigator: 
Gretchen A. Brenes, PhD 
 
Department of Internal Medicine, Section on 
Gerontology and Geriatric Medicine 
 
 
Medical Center Boulevard 
 
 
Winston-Salem, NC 27157 
                                                           Telephone: (336) 716-1103  
 
 
Fax: (336) 716-6830 
 
 
E-mail address: gbrenes@wakehealth.edu  
 
 
 

 
 
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Organization:  
 
 
Wake Forest School of Medicine 
Investigator: 
 
Kathryn Weaver, PhD  
 
 
Department of Social Sciences & Health Policy  
 
 
Division of Public Health Sciences  
 
 
Medical Center Boulevard  
 
 
Winston-Salem, NC 27157  
 
 
Telephone: (336) 716-0891  
 
 
Fax: (336) 713-6476  
 
 
E-mail address: keweaver@wakehealth.edu  
 
Organization:   
 
 
Wake Forest School of Medicine  
Investigator/Protocol Statistician: Janet A. Tooze, PhD 
 
 
Department of Biostatistical Sciences 
 
 
Division of Public Health Sciences  
 
 
Medical Center Boulevard  
 
 
Winston-Salem, NC 27157  
 
 
Telephone: (336) 713-3833 
 
 
Fax: (336) 716-6427 
 
 
E-mail address: jtooze@wakehealth.edu  
 
Organization:   
 
 
Wake Forest School of Medicine  
Investigator: 
 
Rakhee Vaidya, MD 
 
 
Department of Hematology and Oncology 
 
 
Division of Public Health Sciences  
 
 
Medical Center Boulevard  
 
 
Winston-Salem, NC 27157  
 
 
Telephone (336) 713-3833 
 
 
Fax: (336) 716-2774 
 
 
E-mail address: ravaidya@wakehealth.edu  
 
Organization: 
 
University of Alabama 
Investigator 
       Maria Pisu, PhD 
 
 
Division of Preventative Medicine 
 
 
Medical Towers 636 
 
 
1717 11th Avenue South 
 
 
Birmingham, Alabama 35205 
  
 
Telephone: (205) 975-7366 
 
 
Fax: (205) 934-7959 
 
 
E-mail address: mpisu@uab.edu  
 
Organization: 
 
Wake Forest School of Medicine 
Wake Forest RB Statistician:  
Emily V. Dressler, PhD 
 
 
Division of Public Health Sciences 
 
 
Department of Biostatistics and Data Science 
 
 
Medical Center Boulevard 
 
Winston-Salem, NC 27157 
 
Telephone: (336) 716-0917 
 
Fax: (336) 716-6427 
 
E-mail address: edressle@wakehealth.edu 
 
 
  
 
 
 
 

 
 
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Grant #: 1 R21 CA198237-01A1 
 
 
 
Protocol Amendment #: 
5 
Protocol Version Date: 
12/09/2020 
 
Protocol History: 
Initial 
Version 12/21/2017 
Not Activated 
Amendment 1 
Version 03/16/2018 
Activated 06/18/2018 
Amendment 2 
Version 06/22/2018 
Activated 08/10/2018 
Amendment 3 
Version 09/19/2018 
Activated 04/29/2019 
Amendment 4 
Version 11/20/2019 
Activated 04/27/2020 
 
 
 
 
 
 
 
Participating Organizations 
 
NCORP Limited Participation: Wake Forest NCORP Affiliates and Sub-affiliates 
 
 

 
 
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CONTACT INFORMATION 
 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org,            
and select the Regulatory  
Regulatory Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-2878 
to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Please refer to the patient 
enrollment section of the 
protocol for detailed instructions. 
 
Data will be submitted to the WF 
NCORP Research Base.  
 
Address:  
WF NCORP Research Base  
Wake Forest Baptist Medical 
Center  
Building 525@Vine, 4th floor  
Medical Center Boulevard 
Winston-Salem, NC 27157  
 
Fax: (336) 713-6476  
Email: NCORP@wakehealth.edu 
 
Do not submit study data or forms 
to CTSU Data Operations. Do not 
copy the CTSU on data 
submissions. 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page of the CTSU member’s website https://www.ctsu.org.  Access to the 
CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - Identity and 
Access Management (CTEP-IAM) registration system and requires user log on with CTEP-IAM 
username and password. 
For clinical questions (i.e. patient eligibility or treatment-related) contact the Site Coordinator at 
Wake Forest NCORP Research Base at NCORP@wakehealth.edu. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 

 
 
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SCHEMA 
 
 
 
If PHQ-2 <2 and anxiety 
item <1,  
Not eligible for study 
If risk of harm to self and 
others refer for emergency 
room evaluation,           
Not eligible for study 
If No/Mild Symptoms for    
Depressive and Anxiety 
Symptoms,                
provide survivorship 
resources (Supportive Care 
& Prevention)              
Not eligible for study 
Brief initial screen with PHQ-2 and single 
anxiety item 
Determine Depressive 
Symptoms Score (PHQ-9)     
 
Mild: 1-7                   
Moderate: 8-14              
Severe: 15-27 
 
Determine Anxiety 
Symptoms Score (GAD-7)    
 
Mild: 0-9                   
Moderate: 10-14             
Severe: 15-21 
 
 
Screen with PHQ-9 and GAD-7
Stepped-Care   
Telehealth             
Low Intensity 

Self-guided CBT 
(cognitive behavioral 
therapy) workbook 

Bi-weekly check in 
calls with research 
staff  
Enhanced Usual Care        
 (EUC Control)                              

Survivorship resources 

Contact information for local mental health 
providers 
Stepped-Care 
Telehealth             
High Intensity 

Self-guided CBT 
(cognitive-
behavioral therapy) 
workbook 

Weekly CBT by 
telephone with a 
trained therapist
 
Assign to group based on highest level of 
symptom from the PHQ-9 and/or GAD-7 (N=90) 
 
Severe Symptoms    
Randomize 
 
Moderate Symptoms    
Randomize 

 
 
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STUDY SUMMARY 
 
Endpoints: Feasibility (accrual, retention, adherence), anxiety, and depressive symptoms, cost.  
 
Stratification Participants will be stratified by baseline score ≥15 on the GAD-7 and/or on the 
PHQ-9, indicating severe anxiety or depressive symptoms, and by whether they qualified for the 
study by the GAD-7, PHQ-9, or both. 
 
Study Sample: 90 participants 
 
Study Duration: 13 - 15 weeks 
 
Brief Eligibility Criteria: 
 
Age ≥18 years 
 
Score ≥10 on the GAD-7 and/or a score ≥8 on the PHQ-9, indicating clinically significant 
anxiety or depressive symptoms, respectively. 
 
Past history of treated Stage I, II, or III (newly diagnosed or recurrent) of any of the 
following cancers: breast, colorectal, prostate, gynecologic (only uterine and cervical) and 
any stage lymphoma (Hodgkin’s or non-Hodgkin’s).   
 
6-60 months post-treatment completion (surgery, chemotherapy, and/or radiation therapy) 
for cancer. Time frame applies to most recent completion of treatment if participant had a 
cancer recurrence. It is acceptable to be on hormonal therapies. 
 
Participant resides in California, Georgia, Illinois, Kansas, Michigan, Minnesota, 
Missouri, New Mexico, North Carolina, North Dakota, South Carolina, Virginia, 
Tennessee, or Wisconsin.  
 
Study trained therapist in state where participant resides.  
 
Must be able to speak and understand English. 
 
Must have access to a telephone. 
 
 
 
 
 

 
 
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TABLE OF CONTENTS 
SCHEMA ........................................................................................................................................... 5 
STUDY SUMMARY ......................................................................................................................... 6 
1. 
OBJECTIVES .......................................................................................................................... 9 
1.1 
Primary Objectives ......................................................................................................................... 9 
1.2 
Secondary Objectives ..................................................................................................................... 9 
1.3 
Exploratory Objectives ................................................................................................................... 9 
2. 
BACKGROUND ...................................................................................................................... 9 
2.1 
Distress in Cancer Survivors ........................................................................................................... 9 
2.2 
Rationale ....................................................................................................................................... 10 
3. 
SUMMARY OF STUDY PLAN ........................................................................................... 10 
4. 
PARTICIPANT SELECTION ............................................................................................... 11 
4.1 
Inclusion Criteria .......................................................................................................................... 11 
4.2 
Exclusion Criteria ......................................................................................................................... 12 
4.3 
Inclusion of Women and Minorities ............................................................................................. 12 
4.4 
Recruitment and Retention Plan ................................................................................................... 13 
5. 
INTERVENTION PARAMETERS (RETENTION, ADHERENCE, TREATMENT 
FIDELITY) ............................................................................................................................ 14 
5.1 
Study retention .............................................................................................................................. 14 
5.2 
Adherence ..................................................................................................................................... 14 
5.3 
Treatment Fidelity ........................................................................................................................ 14 
5.4 
Management of Study Risk ........................................................................................................... 15 
5.5.   Crisis Protocol .............................................................................................................................. 15 
6.   
REGISTRATION ................................................................................................................... 16 
6.1 
Cancer Therapy Evaluation Program Investigator Registration Procedures ................................. 16 
7. 
CLINICAL EVALUATIONS AND PROCEDURES ........................................................... 19 
7.1 
Intervention Description ............................................................................................................... 19 
7.2.   Schedule of Events ....................................................................................................................... 20 
7.3 
Baseline Testing/Pre-Study Evaluation ........................................................................................ 21 
7.4  
Baseline Testing............................................................................................................................ 24 
7.5 
Participant Enrollment and Randomization .................................................................................. 25 
7.6 
Evaluation During Study Intervention .......................................................................................... 25 
7.7 
Evaluation at Completion of Study Intervention – Week 13 (could occur weeks 13-15 only for 
High Intensity Participants): (visit must be completed between Week 12 and Week 15) ....................... 26 
7.8 
End of Study ................................................................................................................................. 27 
7.9 
Methods for Clinical Procedures .................................................................................................. 27 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION.................................... 29 
8.1 
Primary Endpoint .......................................................................................................................... 29 
8.2 
Secondary Endpoints .................................................................................................................... 29 
8.3 
Off-Study Criteria ......................................................................................................................... 30 
8.4 
Study Termination ........................................................................................................................ 30 
9. 
CORRELATIVE/SPECIAL STUDIES- N/A ........................................................................ 31 
10. 
SPECIMEN MANAGEMENT- N/A ..................................................................................... 31 
11. 
REPORTING ADVERSE AND SERIOUS ADVERSE EVENTS ....................................... 31 
11.1  Reportable Adverse Events ........................................................................................................... 31 
11.2   Serious Adverse Events ................................................................................................................ 31 
11.3  Selected Adverse Events ............................................................................................................... 32 
12. 
STUDY MONITORING ........................................................................................................ 32 
12.1  Data Management ......................................................................................................................... 32 
12.2  Case Report Forms ....................................................................................................................... 32 
12.3  Source Documents ........................................................................................................................ 32 
12.4  Data and Safety Monitoring Plan .................................................................................................. 33 
12.5  Sponsor or FDA Monitoring ......................................................................................................... 33 
12.6  Record Retention .......................................................................................................................... 33 
13. 
STATISTICAL CONSIDERATIONS ................................................................................... 34 
13.1  Study Design/Description ............................................................................................................. 34 

 
 
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13.2  Randomization/Stratification ........................................................................................................ 34 
13.3  Sample Size .................................................................................................................................. 35 
13.4  Primary Objective, Endpoint(s), Analysis Plan ............................................................................ 35 
13.5  Secondary Objectives, Endpoints, Analysis Plans ........................................................................ 35 
13.6  Exploratory Objectives, Endpoints, Analysis Plans ...................................................................... 36 
13.7  Reporting and Exclusions ............................................................................................................. 36 
13.8  Evaluation of Response ................................................................................................................ 37 
REFERENCES ................................................................................................................................ 38 
 
Appendices: 
 
A01 
Addenda 
A02 
Pre-Visit Form 
A03 
Pre-Screening Form 
A04 
Screening Form 
A05a 
BL_Self Report Measures Letter 
A05b 
BL_Self-Report Measures 
A06 
Baseline Interviewer-Administered Measures and Chart Review 
A07 
Enrollment Form 
A08 
Randomization Form 
A09 
CBT Workbook 
A10a 
ERS Ltr Template_High and Low Intensity 
A10b 
Expectancy Rating Scale 
A11 
Week 7 Mid-Assessment Interviewer-Administered Measures 
A12a 
Wk13_Self-Report Measures Ltr 
A12b 
Wk13_Self-Report Measures 
A13 
Week 13 Interviewer-Administered Measures and Chart Review 
A14 
Telephone Script/Manual for Low-Intensity Group 
A15 
Psychotherapy Manual for High-Intensity Group 
A16 
Stepped-Care Telehealth (High Intensity) Progress Note 
A17 
Working Alliance Inventory: Therapist 
A18 
Telehealth Therapist Adherence & Competency Ratings-CBT 
A19 
Low Intensity Check-In Calls Adherence Rating Form 
A20 
EUC Survivor Resources 
A21 
Crisis Protocol and Crisis Protocol Event Form 
A22 
Safety: Adverse Event Form 
A23 
Participant Status Change Form 
A24 
Tracking Log (Implementation Costs) 
A25 
List of Psychotropic Medication 
A26 
Measures and Documents 
 
 
 
 
 
 
 

 
 
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1. 
OBJECTIVES 
 
1.1 
Primary Objectives  
 
1.1.1. To determine feasibility (recruitment, accrual, retention, adherence) of a RCT of a stepped-care 
telehealth mental health intervention (tailored to symptom level) versus enhanced usual care in 90 
post-treatment cancer survivors with moderate or severe levels of emotional distress (anxiety 
and/or depressive symptoms). 
 
1.2 
Secondary Objectives  
 
1.2.1. To obtain preliminary data on the efficacy and variability of a stepped-care telehealth mental 
health intervention (tailored to symptom level) versus enhanced usual care for reducing emotional 
distress (anxiety and/or depressive symptoms) in 90 post-treatment cancer survivors. 
 
1.2.2. To obtain preliminary data on the efficacy and variability of a stepped-care telehealth mental 
health intervention (tailored to symptom level) versus enhanced usual care for secondary 
outcomes (sleep disturbance, fatigue, fear of recurrence, cancer-related distress, and QOL) in 90 
post-treatment cancer survivors. 
 
1.2.3. To determine costs associated with both stepped-care telehealth and enhanced usual care 
interventions from the perspective of a healthcare provider. We will determine costs of 
intervention implementation and health care utilization in all arms over the course of the 
interventions. 
 
1.3 
Exploratory Objectives  
 
1.3.1. To examine potential differential effects of the intervention on anxiety, depression, sleep 
disturbance, fatigue, fear of recurrence, and QOL, by gender, age, race/ethnicity, rural v. urban 
status, stratification arm (moderate, severe), and psychotropic medication use at baseline.  
 
1.3.2 
To examine mediating effects of expectancy ratings of the intervention on anxiety and 
depression. 
 
2. 
BACKGROUND 
 
2.1 
Distress in Cancer Survivors 
 
Psychological concerns are among the most commonly reported unmet needs among post-treatment 
cancer survivors.1 Psychosocial distress, including anxiety and depressive symptoms, is also common.2–14 
Up to 54% of post-treatment cancer survivors report clinically significant distress,4,15 which is associated 
with multiple adverse outcomes, including decreased quality of life (QOL),10,16,17 functional 
limitations,18,19 poor sleep,20,21 increased pain,14 and – particularly for those with elevated depressive 
symptoms – increased mortality.22,23 The Institute of Medicine has emphasized post-treatment 
survivorship as a “distinct phase of cancer care,” with a need for ensuring delivery of appropriate care for 
cancer survivors.24 The need for interventions to reduce psychosocial morbidity in post-treatment cancer 
survivors is critical.6,25 Psychosocial interventions for post-treatment cancer survivors may improve 
mental and physical health, potentially offsetting increased health care costs among distressed cancer 
survivors.26  
 
Mental health issues are more prevalent among the 2.8 million US cancer survivors living in rural 
(versusnon-rural) areas,27 further illustrating how the “burden of cancer is magnified among the US rural 
population.”28 Rural cancer survivors report more mental health concerns than non-rural cancer 

 
 
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survivors,29 yet psychosocial care for cancer survivors is scarce in many rural areas.15,24,28,30 Almost 21% 
of U.S. cancer survivors reside in rural areas,25,27 and over half of rural counties have no mental health 
professionals.31 Recent studies found poorer accessibility to mental health professionals29 and higher 
levels of unmet needs3  in rural cancer survivors. Interventions that are accessible to post-treatment cancer 
survivors experiencing significant distress may reduce this cancer heath disparity. 
 
2.2 
Rationale 
 
Noting the need for evidence-based cancer survivorship care, the American Society of Clinical Oncology 
(ASCO) published guidelines for screening, assessment, and care of psychosocial distress (anxiety, 
depression) in adults with cancer.6 These guidelines recommend screening all adults with cancer for 
distress and treating those with moderate or severe symptoms using a stepped-care approach tailored to 
distress severity. While these guidelines apply to survivors with all cancer types across the cancer 
treatment and survivorship continuum, we have chosen to focus on survivors with non-metastatic breast, 
colorectal, prostate, uterine,  and cervical cancers , as well as those with any stage lymphoma (Hodgkin’s 
or non-Hodgkin’s).  Further, we have focused on the post-treatment survivorship period 6 months-5 years 
post-treatment because distress may be more likely to be assessed and addressed after treatment 
completion. A significant minority of post-treatment survivors is at risk for anxiety and depression 
symptoms during the five years following the end of treatment and accessible interventions are needed to 
treat them. 
 
The purpose of this study is to test a method of implementing this stepped-care approach in community 
oncology practices caring for cancer survivors, using self-directed and stepped-care telehealth approaches 
based on cognitive-behavioral theory. Our approach is based on a previous trial of telephone-based 
cognitive behavioral therapy for rural older adults with Generalized Anxiety Disorder (NIMH 
1R01MH083664: The Tranquil Moments Study; PI: Brenes), which has demonstrated high acceptability 
and efficacy for reducing anxiety, worry, and depressive symptoms in a rural geriatric population.32 This 
protocol adapts the methods of the previous trial to bring psychosocial care to underserved cancer 
survivors, many of whom have minimal or no access to mental health providers. Cancer survivors will be 
recruited through multiple NCI Community Oncology Research Program (NCORP) sites through the 
NCI-funded Wake Forest NCORP Research Base (WF NCORP RB). 
 
We will obtain data on feasibility, outcome variability, and efficacy for designing a subsequent fully 
powered randomized controlled trial (RCT) assessing the effects of the intervention on distress in cancer 
survivors. In the planned larger study, we anticipate that this intervention will: (a) reduce treatment 
barriers for post-treatment cancer survivors; (b) enhance availability of psychosocial treatment (through 
use of telephone sessions and a workbook); and (c) result in reductions in anxiety and depressive 
symptoms in cancer survivors. 
 
3. 
SUMMARY OF STUDY PLAN 
 
This study compares a stepped-care telehealth intervention (tailored to level of symptomatology and 
designed to reduce anxiety and depressive symptoms) with enhanced usual care (EUC). Participants with 
no/mild symptoms will be provided survivorship resources and will not be included in the trial. 
 
A total of 90 participants will be randomized. Study screening will be completed by a Research Nurse or 
an appropriate designated research staff member at each NCORP component. Assuming an accrual rate of 
approximately 8-9 randomized participants per month, we expect study recruitment to be complete within 
11 months. 
 
Referred participants will waive documentation of informed consent to complete the PHQ-2 and single 
anxiety question. If a participant scores ≥ 2 on the PHQ-2 or ≥ 1 on the anxiety question, he/she will be 
invited to complete the full screening assessment to determine study eligibility. The participant will 
complete the Abbreviated Verbal Consent at this point. We are asking to waive the following elements of 

 
 
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consent for this second step of screening: disclosure of appropriate alternatives, statements regarding who 
may access the participant’s medical record for verification, and compensation for injury. If they meet all 
eligibility criteria and want to participate in the randomized trial, they will provide full informed consent 
for study participation. Trained research staff members at each NCORP component will obtain full 
informed consent from all interested and eligible potential participants. 
 
In accordance with ASCO guidelines, participants with no/mild symptoms will be provided with written 
survivorship resources (a letter that contains a link to the National Cancer Institute booklet “Facing 
Forward: Life after Cancer Treatment”) and will not be randomized (Appendix 20). Participants with 
either moderate or severe distress (anxiety or depressive symptoms) will be randomized into stepped-care 
telehealth (tailored to level of symptoms) or EUC. For participants with moderate symptoms (PHQ-9: 8-
14; GAD-7: 10-14), low-intensity stepped-care telehealth will consist of a self-guided cognitive 
behavioral therapy (CBT) workbook to reduce anxiety and depressive symptoms and biweekly (every two 
weeks) check-in calls from research staff at NCORP components. On the biweekly check-in calls, 
research staff from NCORP components will provide minimal support and will administer the scripted 
“Telephone Script/Manual for Low-Intensity Group Check-in Call Form.” This form assesses changes in 
symptom severity during the past two weeks. The site staff person is directed to follow Telehealth crisis 
protocol, refer to Appendix 21, for participants indicating “thoughts of death or suicidal ideation.” Site 
staff should also follow crisis procedures for any other problems identified during administration of the 
form where follow-up is needed.  
 
For participants with severe symptoms (PHQ-9: 15-27; GAD-7: 15-21), high intensity stepped-care 
telehealth will consist of a CBT workbook with accompanying psychotherapy by a Master’s- or doctoral-
level therapist delivered by telephone. Participants randomized to EUC will receive survivorship 
resources (Appendix 20) and referral information for local mental health providers. 
 
4. 
PARTICIPANT SELECTION 
 
4.1 
Inclusion Criteria 
 
4.1.1. Age ≥18 years 
 
4.1.2. Score ≥10 on the GAD-7 and/or a score ≥8 on the PHQ-9, indicating clinically significant anxiety 
or depressive symptoms, respectively. 
 
4.1.3. Past history of treated (newly diagnosed or recurrent)28,29 breast, colorectal, prostate, gynecologic 
(only uterine and cervical) cancers (Stage I, II, or III) or any stage lymphoma (Hodgkin’s or non-
Hodgkin’s).   
 
4.1.4. 6-60 months post-treatment (surgery, chemotherapy, radiation therapy, and/or maintenance 
therapies) for cancer. Time frame applies to most recent completion of treatment if participant 
had a cancer recurrence. It is acceptable to be on hormonal therapies.  
 
4.1.5. Participant resides in California, Georgia, Illinois, Kansas, Michigan, Minnesota, Missouri, New 
Mexico, North Carolina, North Dakota, South Carolina, Virginia, Tennessee, or Wisconsin.  
 
4.1.6. Study-trained therapist in the state where the participant resides.   
 
4.1.7. Must be able to speak and understand English. 
 
4.1.8. Must have access to a telephone. If a patient does not have access to a phone or has difficulty 
paying for minutes for a mobile phone, the research team should contact the Wake Forest 
investigators or site coordinators to arrange for assistance. 
 

 
 
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4.2 
Exclusion Criteria 
 
4.2.1. Current psychotherapy [regular appointment(s) with a psychologist, counselor, or therapist within 
the last 30 days prior to randomization] 
 
4.2.2. Self-reported active alcohol or substance abuse within the last 30 days 
 
4.2.3. Past history of prostate cancer or non-Hodgkin’s lymphoma with only active surveillance (i.e., no 
surgery, chemotherapy, or radiation therapy) 
 
4.2.4. Progressive cancer (must be considered no evidence of disease or stable)  
 
4.2.6. Self-reported psychotic symptoms in the last 30 days prior to randomization (See item in 
Appendix 4: “Have you seen things that aren’t really there or have you heard voices when no one 
else was around within the last 30 days?”) 
 
4.2.7. Active suicidal ideation with plan and intent 
 
4.2.8. Any change in psychotropic medications within the last 30 days (See Appendix 25) 
 
4.2.9. Hearing loss that would preclude participating in telephone sessions (determined by brief hearing 
assessment administered by research staff at each NCORP component). Individuals who can 
compensate for hearing loss through the use of a hearing device or TDD phone, and through the 
use of such devices are able to communicate with the study therapist by telephone, will be 
included. If the therapist cannot communicate with the participant by telephone, the participant 
will be excluded.  
 
4.2.10. Failure/inability/unwillingness to provide names and contact information for two family members 
or friends to serve as emergency contacts during the course of the study 
 
4.3 
Inclusion of Women and Minorities 
 
Both men and women (as applicable) and members of all races and ethnic groups are eligible for this trial.  
 
 
 
 
 
 
  
Females Males Total
 Ethnic 
  
  
  
Hispanic 
8 
7 
15
Not Hispanic 
40 
35 
75
ETHNIC 
TOTAL 
48 
42 
90
  
 Females Males Total
Racial 
  
  
  
Am Indian 
1 
0 
1
Asian 
2 
1 
3
Native 
Hawaiian 
0 
0 
0
Black 
6 
9 
15
White 
39 
32 
71
RACIAL 
TOTAL 
48 
42 
90

 
 
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4.4 
Recruitment and Retention Plan 
 
Participants will be followed for 13 - 15 weeks. After the Week 13 visit (for participants in the 
intervention group, Week 13 measures should be completed after the intervention is finished and could be 
Weeks 13 – 15), the participant is no longer followed and data are no longer collected from the 
participant. 
 
NCORP sites will accrue to this trial through the National Cancer Institute NCORP program. The WF 
NCORP RB will sponsor and administer this trial. There will be a secure, password protected 
TELEHEALTH study website for the management of study participants including randomization, 
schedule of study visits and data entry of forms designated to be entered by site staff.  Data reports and 
documents will also be available.   
 
Potential participants may be recruited via (1) in-clinic screening during medical appointments; (2) 
identifying survivors through the site cancer registry; (3) screening clinic charts; and (4) participant 
recruitment flyers (Support Document 5) and recruitment letters (Support Document 4).  Local sites 
should check with their IRBs to determine if a  partial HIPAA waiver is required for the review of 
participant medical records/charts.  Survivors will be approached in-person or by telephone by NCORP 
staff to ascertain interest and initial eligibility. We will track numbers of survivors approached and 
screened, reasons for nonparticipation, and number randomized. All written materials will be at an 8th 
grade reading level. 
 
We expect to recruit minority participants through several strategies. (1) We will request review of our 
protocol and recruitment materials from the Wake Forest Baptist Comprehensive Cancer Center Cancer 
Office of Cancer Health Equity (for whom Dr. Weaver serves as an Assistant Director) and the Wake 
Forest NCORP Research Base (WF NCORP RB) for suggestions to enhance the appeal of our study to 
minority participants. (2) We will inform all Minority-Underserved NCORPs affiliated with the WF 
NCORP RB in targeted states about the study and seek their feedback on how to enhance minority 
recruitment. Working with Dr. Glenn Lesser, PI of the WF NCORP RB, we will additionally reach out to 
Minority-based NCORPs not currently affiliated with Wake Forest, but with components/sub-components 
in targeted states and encourage them to participate in this study. (3) We will emphasize the importance 
of robust minority accrual at our study kickoff meetings and provide specific education and discussion 
about strategies to overcome barriers that underserved patients may experience to study participation.  (4) 
We will monitor minority recruitment rates at our monthly WF NCORP RB executive committee 
meetings and provide feedback to the NCORP sites via bimonthly study teleconference calls. Specifically, 
we will monitor the minority recruitment rate in conjunction with available data about the population of 
eligible patients at the site to identify sites that are potentially under-performing with regard to minority 
accrual. Sites with strong minority recruitment will be asked to share their experiences with other sites 
during these calls.  
 
Several elements of this trial were designed with retention in mind. First, the follow-up period is brief, 
with total study enrollment lasting only 13 – 15 weeks. Second, the stepped-care telehealth group will 
receive weekly or biweekly (every two weeks) calls from research staff at NCORP components or 
therapists. We will send thank-you letters to the enhanced usual care group following their assessments at 
baseline and 7 weeks (Support document 6). Finally, if a participant does not have a telephone or is 
unable to purchase minutes for their mobile phone to participate in the study intervention or assessments, 
the research team should contact the Wake Forest investigators or site coordinators to arrange for 
assistance. 
 
 
 
 

 
 
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5. 
INTERVENTION PARAMETERS (RETENTION, ADHERENCE, TREATMENT 
FIDELITY) 
 
5.1 
Study retention 
 
Study retention will be estimated by the proportion of participants who complete the Week 7 and 13 
visits.  
 
5.2 
Adherence  
 
Adherence will be recorded as the percentage of therapy sessions (for the high-intensity intervention 
group) or check-in calls (for the low-intensity intervention group) each participant completes.  
 
5.3 
Treatment Fidelity 
 
For the purposes of the study, therapists (who may or may not be employees at NCORP component sites) 
are considered to be research therapists and will contract (or subcontract) with the study to directly 
provide services for the research grant.  As part of the contract, research therapists will be required to 
meet quality metrics including the audiotaping of psychotherapy sessions to ensure treatment fidelity.  All 
therapy sessions will be audiotaped, and 8% of psychotherapy sessions (1 session per randomized 
participant) will be randomly selected for review (not live) by Dr. Brenes using a measure of therapist 
adherence (Appendix 18) and competence developed and used by Stanley and colleagues (Stanley et al., 
1996; Stanley et al., 2003).  This measure assesses both the competence and adherence of the therapist in 
the delivery of the specific skills of the intervention (e.g., progressive muscle relaxation, problem solving, 
etc.) as well as an overall rating of therapist competence and adherence.  Data suggest high internal 
consistency (alpha = .91-.94) and greater variability in ratings attributed to clinicians (29%) than raters 
(9%), suggesting good reliability of the instruments (personal communication, Dr. Melinda Stanley; see 
Appendix 18 for a copy of this measure.)   
 
Local site staff that are part of the research team and are responsible for making check-in calls with study 
participants will be audio-taped for adherence to study protocol and competence.  All check-in calls will 
be audiotaped and 16% of calls (1 session per participant) will be randomly selected for review (not live) 
by Dr. Danhauer using a measure of adherence and competence developed for this study (see Appendix 
19 for a copy of this measure.)  Dr. Danhauer will meet via telephone with the research staff whose 
ratings indicate difficulties in intervention delivery.  
 
Therapists (CBT)/research staff (check-in calls) who do not demonstrate competency (competency score 
< 6) will receive additional training until competency is demonstrated.  Dr. Brenes will meet with 
therapists on a regular basis to discuss cases, review therapist adherence and competence ratings, and 
answer questions regarding protocol administration. Any areas of nonadherence will be reviewed, and the 
therapist will review any difficulties in intervention delivery.  
 
The primary purpose of the data collected from the audiotaped therapy sessions and check-in calls is to 
identify research personnel who are not implementing the protocol/intervention with fidelity and to 
provide these personnel with additional supervision and/or training to improve protocol adherence.  This 
is a common approach used in clinical trials of psychotherapy and behavioral interventions. The study 
will not use aggregate data from the audiotaped sessions/calls as a feasibility/adoption metric.      
 
Study therapists will meet regularly with Drs. Brenes or Danhauer for ongoing discussion of cases and 
study supervision. 
 
 
 

 
 
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5.4 
Management of Study Risk 
 
The following procedures are in place to protect against possible risks:  
 
Participants who are at high risk for adverse outcomes (e.g., active suicidal ideation with plan and intent, 
current psychosis) will be excluded from the study. Participants who do not meet study inclusion criteria 
will be provided with alternative referrals. If any participant shows evidence of the need for immediate 
treatment (e.g., active psychosis, suicidal intent) at any time during the consent, assessment, and 
treatment periods, the participant will be referred for immediate psychiatric assistance (as specified in the 
Crisis Protocol, Appendix 21), and one of the co-PIs will be notified. 
 
The only risk of this study is that some individuals may find discussing their problems with others to be 
uncomfortable, embarrassing, and/or stressful. This is expected to be temporary. All study staff will be 
trained to deal with these situations, and every effort will be made to address each participant’s concerns 
or problems in the most supportive, empathic, and therapeutic manner. 
 
5.5.  
Crisis Protocol 
 
If any participant indicates a significant worsening in anxiety or depression scores (1 standard deviation 
increase (rounded to the nearest integer) on the GAD-7 (Change≥4)75 or PHQ-9 (Change≥6)73 from 
baseline) or the participant expressed suicidal ideation on the PHQ-9 (Question 9 score of >2), the 
computer software system will automatically generate an e-mail to the co-PIs and the Wake Forest School 
of Medicine Project Manager. The co-PIs or Project Manager will follow up with staff (either the 
therapists for participants in the high-intensity stepped-care telehealth or site personnel for participants in 
the low-intensity stepped-care telehealth or usual care arms) to enact the Crisis Protocol and complete a 
Crisis Protocol Event Form.  During the course of a regularly scheduled participant contact, it may 
become evident that there is a need for immediate evaluation. (e.g., active suicidal ideation, active 
psychotic symptoms, disorientation). Staff will be instructed to follow the Crisis Protocol and complete 
the Crisis Protocol Event Form. In both cases, the participant may be referred for psychiatric care by their 
primary care physician or by an emergency department physician.  
 
Study staff will follow the steps outlined in the Crisis Protocol and participants will receive information 
about safety precautions and procedures to follow in the event of a crisis (i.e., the participant becomes 
imminently suicidal).  Because active suicidal ideation is an exclusion criterion for the study, we 
anticipate that the risk of participants becoming suicidal during the study will be minimal. Further, based 
on our prior studies, no participants randomized into the study became imminently suicidal. All study 
staff (therapists, site staff) will receive training on the Crisis Protocol and coping with participant distress 
that may be experienced during the consent, assessment and treatment procedures.  In addition, sites will 
have regular study team meetings to discuss clinical issues.  Dr. Brenes will review the status and 
progress of participants with the study therapists on a regular (at least monthly) basis.  All participants 
will be contacted at Week 7 to assess the primary outcomes and depressive symptoms. Additionally, 
study therapists will attempt to reach participants who miss a session by calling the participant twice in a 
one-week period. If the therapist is unable to contact the participant by phone, the therapist will send the 
participant a letter by mail with a request that the participant contact the therapist regarding interest in 
continuing the study sessions.  
 
5.5.1. Emergency Contacts 
 
As an additional safety precaution and part of the screening, participants will provide the names of two 
emergency contacts and their phone numbers. Study staff will contact the emergency contacts if needed 
during the administration of the Crisis Protocol or in any other emergency. If the Crisis Protocol is 
activated during a study session or contact and the participant misses the next scheduled session, then the 
therapist will call the emergency contacts immediately.    

 
 
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6.   
REGISTRATION 
 
6.1 
Investigator and Research Associate Registration  with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually.  To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) https://ctepcore.nci.nih.gov/rcr.  
RCR utilizes five person registration types. 
 
IVR — MD, DO, or international equivalent; 
 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications such as the Roster Update Management System [RUMS], OPEN, 
Rave, acting as a primary site contact, or with consenting privileges; 
 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) 
with limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR
NPIVR
AP
A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
 
 
 
 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access 
all CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards 
(IRBs) covering their practice sites on the FDA Form 1572 in RCR to allow the following: 
 Addition to a site roster 
 Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
 Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
 Assign the Clinical Investigator (CI) role of the Delegation of Tasks Log (DTL) 

 
 
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In addition, all investigators act as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the 
DTL must be rostered at the enrolling site with a participating organization.  
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact 
the RCR Help Desk by email at  RCRHelpDesk@nih.gov. 
 
6.2 
Cancer Trials Support Unit Registration Procedures 
 
Protocol documents are found on the CTSU website, but additional supplemental 
documents may be available on the Wake Forest NCORP Research Base website 
(https://wakencorp.phs.wakehealth.edu/dspLogin.cfm). 
 
This study is supported by the NCI CTSU. 
 
IRB Approval:   
 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was previously open at the 
site under the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local 
Context (SSW) to the CIRB using IRBManager to indicate their intent to open the study locally. 
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office by 
emailing the email address above or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB approval 
record to be completed: 
 
Holds an Active CTEP status; 
 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) 
and on at least one participating roster; 
 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; and 
 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
 
Additional requirements to obtain an approved site registration status include: 
 
An active Federal Wide Assurance (FWA) number; 

 
 
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 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO); and 
 
Compliance with all protocol-specific requirements (PSRs). 
 
6.3 
Protocol Specific Requirements for WF-30917CD Site Registration: 
 
 NCI CIRB approval – all participating sites must use the NCI CIRB as their IRB of record for 
WF-30917CD.   
 Confirmed study-trained therapist for the state in which the site is located who has completed 
protocol specific training. 
 Site Open to Enrollment (SOTE) letter from WF NCORP RB, which is provided to the site 
once all start-up activities have been completed. 
 
Practice Level Data Collection Form – The enrolling affiliate/sub affiliate will complete 
the NCORP Practice Level Data Collection Form and submit it to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. The form will collect various attributes about the enrolling affiliate/sub 
affiliate. All of the questions on the form must be complete and the distribution for the 
analytic cases question must equal 100%. (See form for directions.) The form must be 
received and complete for site registration approval in RSS. The Practice Level Data 
Collection Form requirement is submitted once for participation on all NCORP Cancer 
Care Delivery (CCDR) trials, but will expire two years after it is received. NCORP sites 
will need to resubmit the Practice Level Data Form to the CTSU in order to continue to 
enroll to CCDR trials.  
 
6.4 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  
 
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission.    
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 
6.5 
Checking Your Site’s Registration Status: 
 
Site registration status may be verified on the CTSU member’s website.  
 
 
Click on Regulatory at the top of the screen; 
 
Click on Site Registration; and 
 
Enter the sites 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol Status, 
and/or IRB Type 
 
Note: The status shown only reflects institutional compliance with site registration requirements 
as outlined above. It does not reflect compliance with protocol requirements for individuals 
participating on the protocol or the enrolling investigator’s status with the NCI or their affiliated 
networks. 
 

 
 
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7. 
CLINICAL EVALUATIONS AND PROCEDURES 
 
7.1 
Intervention Description 
 
Participants with moderate anxiety and depressive symptoms will be randomized to either the low-
intensity stepped-care telehealth or the EUC control.  Participants with severe symptoms will be 
randomized to either the high-intensity stepped-care telehealth intervention or the EUC control. 
Therapists participating in the trial must meet the following requirements: a Master’s or doctoral degree 
in counseling, marriage and family therapy, psychology, or social work; licensed as an independent 
mental health provider in California, Georgia, Illinois, Kansas, Michigan, Minnesota, Missouri, New 
Mexico, North Carolina, North Dakota, South Carolina, Virginia, Tennessee, or Wisconsin; and 
experience with cognitive-behavioral therapy.  Experience working with oncology patients/survivors is 
preferred. Therapists will attend a 1.5-day training that will cover information on study design, anxiety 
and depression in cancer survivors, principles of cognitive-behavioral therapy, delivery of the 
intervention, and use of the web-based data-entry system. NCORP sites and/or components may nominate 
therapists for participation, but are not required to identify a therapist to participate. The Wake Forest 
study team will identify a participating therapist for each state. 
 
Low Intensity Stepped-care Telehealth: The low-intensity stepped-care telehealth group will consist of a 
self-guided CBT workbook (15 minutes daily to read and complete exercises/homework) and biweekly 
(every two weeks) check-in calls (5-10 minutes) from an NCORP component research staff person to 
assess changes in symptom severity/immediate need for psychiatric treatment and provide minimal 
support. Check-in calls are expected to be completed within +/- 2 days of the window specified in the 
Telehealth website; however, check-in calls up to +/- 1 week of the window are permitted. 
 
Consistent the ASCO guidelines,37 the Wake Forest NCORP Research Base staff will mail a 
professionally-prepared and IRB-approved CBT workbook to participants that focuses on different 
cognitive-behavioral techniques for managing anxiety, depression, and distress. CBT teaches people to 
monitor depressive and anxiety-producing thoughts, modify these thoughts, and modify behaviors that 
reinforce depression and anxiety. Chapters focus on the cognitive-behavioral model of depression and 
anxiety, relaxation techniques, cognitive restructuring, problem solving, worry control, exposure, 
behavioral activation, and relapse prevention.  
 
All participants receive 10 identical chapters.  To tailor the intervention to anxiety and depressive 
symptoms, participants are instructed to choose 2 chapters from a menu of 5 chapters (e.g. pain, more 
focused information on changing behavior related to anxiety or depression, etc.).  Workbook chapters 
target issues specific to cancer survivors, such as (a) fear of recurrence (most commonly reported source 
of distress in survivors across different types of cancer);8,9,13,24,38–48 (b) lasting effects of treatment on 
health, ongoing symptoms of fatigue and physiologic effects of cancer treatment;38,39,42,44,48–50 (c) late 
effects of cancer treatment (the possibility of developing other diseases);14,38,45 (d) concerns about 
reproductive ability and higher risk of cancer for their children;50,51 and (e) distress related to changes in 
body image and sexuality.14,41,45 These participants will also receive biweekly (every two weeks) check-in 
calls from a research staff person at NCORP components to provide support and assess symptom severity 
changes (Appendix 14). Participants with increased symptoms as indicated by 1 standard deviation 
increase and a total score of ≥15 on either the PHQ-9 or GAD-7 at Week 7 will be moved to the high-
intensity treatment or referred for more intensive psychiatric treatment (per the Crisis Protocol, see 
Appendix 21). If participants are moved from the low intensity to high intensity treatment, the Participant 
Status Change Form should be completed (Appendix 23).  Analysis will proceed as intent-to-treat with 
their initial stepped-care telehealth level; we do not anticipate that many people will change from 
moderate to severe during the study. 
 
High Intensity Stepped-care Telehealth: The high-intensity stepped-care telehealth group will consist of 
the CBT workbook (15 minutes daily to complete exercises/homework), plus psychotherapy delivered by 
telephone with a licensed therapist (45 minute sessions weekly). If participant is randomized to the High 

 
 
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Intensity Arm, the therapist will make at least one attempt to schedule the participant’s first therapy 
session within 2 weeks of the date of notification via email. 
 
Consistent with the ASCO guidelines,37 the Wake Forest NCORP Research Base staff will mail a 
professionally prepared and IRB approved CBT workbook to participants and participants will have 12 
weekly therapy sessions with the study therapist. The study therapist will be a licensed mental health 
provider (e.g., licensed clinical social worker, marriage and family therapist, licensed professional 
counselor, psychologist). Onsite or phone training is provided for all participating therapists. Training 
will include the use of the workbook, formal didactic presentations, readings, and role-plays. All study 
therapists will receive regular (at least monthly) study supervision from Dr. Brenes. There will be at least 
one trained therapist for each state in the U.S. that has any participating sites. Each week, the participant 
will receive one 45-minute telephone session and one workbook chapter. The sessions will supplement 
the participant's understanding of anxiety, depression, and distress management techniques and include a 
review of the daily workbook exercises to assure understanding and maximize application in daily life. 
 
Enhanced Usual Care. At the time of randomization, EUC participants will receive: (1) information about 
referrals/resources (Sample Resource Sheet) in their local area, including support groups and mental 
health providers (Appendix 20 and Support Document 9); (2) information about written self-help 
resources (several readily available published workbooks) for anxiety and depressive symptoms; and (3) a 
copy of the National Cancer Institute publication entitled “Facing Forward: Life after Cancer Treatment.” 
This publication can be viewed at the following web link: https://www.cancer.gov/publications/patient-
education/life-after-treatment.pdf. Site staff should contact the NCORP Research Base site coordinator 
who will ship a copy of the booklet to each EUC participant within two weeks of randomization. It 
addresses the topics of follow up medical care, physical changes, body changes and intimacy, feelings, 
and social and work relationships. Upon completion of the Week 13 post-intervention assessment battery, 
the Wake Forest NCORP Research Base staff will send a black and white 2-sided copy of the CBT 
workbook to participants in EUC (same workbook provided to participants in the low-intensity and high-
intensity intervention groups). In addition, the EUC randomization script can be used to help explain EUC 
to participants who are randomized to the EUC condition.  
 
7.2.  
Schedule of Events 
 
NCORP site or component site staff is responsible for printing and mailing all study assessments and 
forms to be completed by the participant if forms are not completed by participants at the site.  A self-
addressed stamped envelope will be provided by the local site for the mailing of the signed consent form 
and all study assessment forms to the local clinical site.  Participants can also opt to scan and email or text 
the signed consent form; however, participants cannot opt to scan and email or text study assessment 
forms.  It is anticipated that there will be <10 participants per state which will keep site costs reasonable.  
Study assessment and data collection information are provided in subsequent sections. 
 
All participants will complete pre- and post-intervention assessments with primary outcomes additionally 
assessed at mid-intervention (Week 7).  The PHQ-9 and GAD-7 may be administered by telephone. 
 
Participants receiving the high-intensity stepped-care telehealth intervention will be reminded during their 
last session that they will receive a post-intervention questionnaire packet via mail. Participants in the 
EUC group will receive an e-mail or telephone reminder (per their preference) that they will receive 
questionnaire packets via mail. If study questionnaires are not received within 2 weeks of the documented 
mail date, the NCORP site research staff will contact participants via telephone or email. If participants 
cannot be reached within 3 days by phone or email, the NCORP site research staff will mail another 
questionnaire packet. If there is still no response within two weeks of mailing the additional set of post-
intervention questionnaires, participants will be contacted via phone and offered the opportunity to 
complete the post-intervention questionnaires by phone.  
 
 

 
 
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7.3 
Baseline Testing/Pre-Study Evaluation 
 
7.3.1. Rationale for Multi-Step Consent Process  
 
We anticipate that a large proportion of the potential participants whom we screen may be 
ineligible for the study. To minimize burden and be most considerate of participants’ time, we 
plan to implement a multi-step consent process as described below. Essentially, we will describe 
as much information as needed to obtain critical screening information and only fully explain the 
entire study to participants who meet eligibility criteria. In brief, we plan to proceed as follows 
(see schema below): (1) Prior to the pre-screening visit, the potential participant’s name, contact 
information, demographics and chart information for eligibility criteria will be collected on a Pre-
Visit Form (Appendix 2) that will be reviewed with potential participants during the pre-
screening visit; (2) Brief pre-screening visit with a waiver of documentation of informed consent, 
a 3-item depression/anxiety screening, an item to determine adequate hearing ability, determine if 
they have access to a phone, understand English and review of the previously collected contact 
information, demographics and basic information about cancer diagnosis and treatment 
(enrollment criteria); (3) Full study screening with the Abbreviated Verbal Consent to include the 
full PHQ-9 and GAD-7. . The abbreviated consent will explain the screening process without 
details of the full study; and (4) Full informed consent will then take place for any potential 
participants who meet all eligibility criteria in the first two steps described here. If the participant 
is present in person, all of these steps may be completed in the same visit.  
 
 
 

 
 
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Schema of Three-Step Consent Process 
  
 

 
 
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7.3.2. Pre-Visit Form 
 
For potential participants who are eligible to be contacted for the Pre-Screening visit, the Pre 
Visit Form will be completed on paper prior to the Pre-Screening visit to streamline the multistep 
screening process.  This form includes their full name, contact information (phone number, 
address), demographics and chart information (eligibility criteria – type of cancer, month/year of 
diagnosis, cancer stage at time of diagnosis, time of last treatment, date of birth, residency zip 
code).  Sites should track Pre-Visit Form completion internally.  This information will not be 
entered into the Telehealth website at the time this information is collected.  It is important to 
retain contact information on the Pre-Visit Form so that sites can verify contact information 
during the Pre-Screening visit.  This step is important when recruiting for a study of depression 
and anxiety as study staff may encounter someone who is suicidal and will need to take steps to 
ensure safety.   
 
7.3.3. Pre-Screening  
 
Referred participants will be invited to complete pre-screening for this study.  If site staff are 
unable to make the initial pre-screening invite contact after 5 attempts, the referred participant 
will be considered a passive refusal and will no longer be contacted by site staff. If pre-screening 
is scheduled for a later date and the referred participant cannot be re-contacted after 5 attempts, 
the referred participant will be considered a passive refusal and will no longer be contacted by 
site staff.  For referred participants who are considered a passive refusal, site staff will be asked to 
enter only race, ethnicity, cancer type, cancer stage, year of birth, and contact attempts into the 
Telehealth website. 
 
Participants who accept the study invite will be asked to provide a verbal waiver of 
documentation of informed consent to complete pre-screening call or visit.  If a participant 
provides verbal consent, the Pre-Visit Form will be reviewed with participants to confirm contact 
information, demographics and chart information (eligibility criteria – type of cancer, month/year 
of diagnosis, cancer stage at time of diagnosis, time of last treatment, date of birth, residency zip 
code).  Participants will also be asked to complete the PHQ-2, 1 anxiety question, and additional 
questions to further pre-screen for additional eligibility criteria including an item to determine 
adequate hearing ability (please refer to the next paragraph for additional hearing ability 
information), telephone access and English language fluency.  Pre-Screening information will be 
collected on paper forms.  This information will not be entered into the Telehealth website at the 
time Pre-Screening information is collected. 
 
To determine adequate hearing ability, the participant is asked to repeat the phrase, “I have a cat 
so all I need is a dog.”  If the participant is able to repeat, staff will continue with screening.  If 
the participant is unable to repeat after a second attempt or if staff thinks hearing is a problem, the 
participant is ineligible and will not be screened further.  Participants with a circumstance that 
could affect the ability to hear at the time of the call (illness, hearing aid problem, in process of 
obtaining hearing aid, etc.) can reschedule.  It is suggested that participants who are screened at 
the site call the site staff from their cell phone or other site/clinic phone. 
 
If someone declines pre-screening or is ineligible after pre-screening, no Protected Health 
Information (PHI) will be entered into the Telehealth website.  For individuals who do not 
proceed to full screening, staff will be asked to enter only race, ethnicity, cancer type, cancer 
stage, and year of birth from the Pre-Visit Form into the Telehealth website.  A PID will be 
assigned at this time.  All information collected on the Pre-Screen Form will be entered in the 
Telehealth website. 
 
 

 
 
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If a participant meets the eligibility criteria based on responses to the questions and scores ≥ 2 on 
the PHQ-2 or ≥ 1 on the anxiety question, they will be invited to participate in the full screening 
assessment to determine eligibility for the study. In order to complete the full screening, sites will 
administer the abbreviated verbal consent.  It is recommended that the screening immediately 
follow the pre-screening; however, there is no time limit between the Pre-Screening and 
Screening visits.  For those who agree to  the abbreviated verbal consent for full screening, all 
data from the Pre-Visit Form and Pre-Screening will be entered into the Telehealth website.  A 
PID will be assigned at this time. 
 
7.3.4. Full Screening 
 
If a participant meets the eligibility criteria on the pre-screen, the participant will be asked to 
complete the Abbreviated Verbal Consent for full screening. Once a participant has agreed to  the 
abbreviated verbal  consent, emergency contact information will be collected and the PHQ-9 and 
GAD-7 will be administered. If the participant is eligible based on the scoring of the PHQ-9 and 
GAD-7, then additional screening questions will be administered.  
 
 
 The PHQ-9 is a nine-item self-report measure used for screening, diagnosing, monitoring and 
measuring the severity of depression that incorporates DSM-IV depression diagnostic criteria. 
A score ≥ 8 indicates moderate depressive symptoms, and a score ≥15 suggests severe 
depressive symptoms 
 
 The GAD-7 is a seven-item self-report measure that incorporates DSM-IV symptoms for 
generalized anxiety disorder. A score ≥ 10 indicates moderate anxiety symptoms, and a score 
≥ 15 suggests severe symptoms. 
 
 
All pre-screening and/or screening steps may be completed in one visit or phone call. If done in 
person, the anxiety question, PHQ-2, PHQ-9 and GAD-7 are to be interviewer administered, and 
there should not be any missing data on these forms.  
 
Subjects who agree to the  abbreviated verbal consent and do not complete the full screening at 
this time will be  contacted up to 5 more times by the site staff.  After 5 contact attempts the 
subject will be considered lost to follow-up and will be considered a screen fail, unless the 
subjects re-contacts the site.  Site staff will enter any screening information collected in the 
Telehealth website.   
 
Randomization must happen within 30 days of screening. If more than 30 days has passed, the 
full screening assessment should be re-administered. 
 
7.3.5. Full Informed Consent 
 
If the participant is eligible based on the screening visit responses and is willing to participate, the 
full informed consent for study participation should be administered. 
 
If a participant is not eligible or declines study participation at screening, site staff will enter 
screening information in the Telehealth website up to the point the participant was no longer 
eligible or declined, and no further information will be collected. 
 
7.4  
Baseline Testing 
 
If full informed consent was administered by phone, the site must receive the signed full informed 
consent prior to initiating baseline study activities. Baseline Interviewer-Administered Measures and 
Chart Review must be administered and completed by site staff.  Baseline Self-Administered Measures 

 
 
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may be completed by the participant at the site or site staff may choose to mail baseline self-administered 
measures to the participant  with a request that they be returned as soon as possible and within two weeks 
(see Section 7.2).  If the self-administered measures are mailed to a participant, site staff may call the 
participant to collect self-administered baseline responses by phone. Randomization must happen after 
baseline assessments but within 30 days of screening.  Replacement packets can be mailed or emailed at 
participant request. The sites must receive the following self-administered completed forms from the 
participant prior to enrolling and randomizing the participant.  
 
Self-Administered Measures (Appendix 5a/5b): 
 
 Demographics and Health Behaviors 
 Fear of Recurrence Inventory--Severity Subscale 
 Insomnia Severity Index 
 PROMIS – Fatigue Scale – Short Form 8a 
 SF–36 Health Survey 
 Impact of Events Scale–Revised 
 Satisfaction with Medical/Mental Health services 
 
Interviewer Administered Measures and Chart Review (Appendix 6): 
 
NCORP component research staff will administer the following forms (see Appendices) by telephone (or 
in person if participant is in clinic) and enter the data on the study website as the data are collected.  
These forms are to be interviewer-administered whether the contact is by telephone or in person.  
The PHQ-9 and GAD-7 should have no missing data.   
 PHQ-9 (administer only if it has been >30 days since screening to reassess eligibility) 
 GAD-7 (administer only if it has been >30 days since screening to reassess eligibility) 
 Charlson Comorbidity Index  
 Cornell Services Index 
 Current Medication Use 
 
Chart Review: 
 Initial Cancer Diagnosis and Treatment Form 
 Additional Malignancy Diagnosis and Treatment Form 
 Cancer Relapse/Recurrence Form 
 
7.5 
Participant Enrollment and Randomization 
 
The electronic participant enrollment form (Appendix 7) will be completed on the day of 
randomization in the Telehealth study website.  The subject should not be randomized and 
enrollment form completed until the subject is ready to start the intervention.  Review the 
Appendix 5a/5b (Baseline Self-Report Measures) for completeness before randomization. Once 
the participant is randomized, the study timeline begins.  A participant will not be considered 
enrolled if they are not randomized to a study arm. Following randomization, the Randomization 
Form should be completed (Appendix 8). 
 
7.6 
Evaluation During Study Intervention 
 
Weeks 1-12:  
 High Intensity Week 1/Low Intensity Week 2:  The Expectancy Rating Scale and 
instructions (Appendix 10a/b) will only be mailed to participants who are randomized to either 
the Low Intensity or the High Intensity intervention groups. Participants are to complete this 
Expectancy Rating Scale after they have completed Chapter 1 of the Cognitive Behavior 
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 Enhanced Usual Care participants will not be mailed the Expectancy Rating Letter or Scale. 
 Enhanced Usual Care participants will be mailed a “Thank You” letter at baseline (Support 
Document 6). 
 Stepped-Care Telehealth (High Intensity) Progress Notes (Appendix 16)/Session Information 
Form (session completed Y/N) (Entered by therapist or NCORP component research staff on 
study website within 48 hours of therapy or check-in sessions) 
 Telephone Script/Manual for Low Intensity Bi-Weekly (every two weeks) Check-In Call Form 
(Appendix 14).  
 Implementation costs (tracking logs) (Appendix 24) 
 
Week 7: (visit must be completed between Week 6 and Week 11) 
NCORP component research staff will administer the following mid-intervention assessments by telephone 
and enter in the study website (Appendix 11).   
 PHQ-9   
 GAD-7  
 Current Medication Use (Update) 
 Adverse Event Ascertainment Form 
 Mid-intervention letter mailed to Enhanced Usual Care participants only (Support Document 
6). 
 
7.7 
Evaluation at Completion of Study Intervention – Week 13 (could occur weeks 13-15 only 
for High Intensity Participants): (visit must be completed between Week 12 and Week 15) 
 
Self-Administered Measures (Appendix 12a/b): 
 
Participants will be mailed the following self-report post-intervention measures with a request that they 
be returned within two weeks. 
 Fear of Recurrence Inventory--Severity Subscale 
 Insomnia Severity Index 
 PROMIS Fatigue Scale- Short Form 8a 
 SF-36 Health Survey 
 Impact of Events Scale – Revised 
 Client Satisfaction Questionnaire 
 Working Alliance Inventory-Participant (high-intensity participants only) 
 Expectancy Rating Scale (low intensity and high intensity participants only) 
 
Interviewer Administered Measures and Chart Review (Appendix 13): 
 
NCORP component research staff will administer the following post-intervention measures by telephone 
and enter on the study website:   
 PHQ-9 
 GAD-7 
 Cornell Services Index 
 Current Medication Use (Update) 
 Adverse Event Ascertainment Form 
 
 

 
 
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Chart Review: 
 Cancer Relapse/Recurrence Form 
 
After all therapy sessions with each participant have been completed, the therapist will complete the 
Working Alliance Inventory-Therapist form (Appendix 17). The Working Alliance Inventory is a process 
measure to evaluate the potential impact of the telehealth intervention on the therapist-participant 
relationship. 
 
7.8 
End of Study 
 
Upon completion of study visits, the Participant Completion Letter (Support Document 3) and the 
Resource Sheet (Support Document 9) will be mailed to participants in the Low Intensity and High 
Intensity groups. 
 
 
7.9 
Methods for Clinical Procedures 
 
The Study Parameter Table (below) indicates the timing, mode of administration, and person who 
administers every aspect of the study. 
 
 

 
 
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Study Parameter Table 
 
Recruitment/             
Chart Review 
Pre-Screen 
Verbal Consent 
Full Screen 
Full Informed  
Consent 
Baseline 
Enrollment/ 
Randomization (wk0) 
Weeks 1-13 
Post Week 13 
Arm 
Wk1 or 2 
W7 
W13 
NCORP Component Site Staff Responsibility 
Mail Recruitment Documentation*  
As 
needed
 
 
 
 
 
 
 
 
 
 
--- 
Pre-Visit Form (Appx 2) 
X 
 
 
 
 
 
 
 
 
 
 
--- 
Pre-Screening Form (Appx 3)* 
 
Xa 
 
 
 
 
 
 
 
 
 
--- 
Abbreviated Verbal Consent 
 
 
Xa 
 
 
 
 
 
 
 
 
--- 
Screening Form (Appx 4)* 
 
 
 
Xa 
 
 
 
 
 
 
 
--- 
Full Informed Consent 
 
 
 
 
Xa 
 
 
 
 
 
 
--- 
Baseline Self-Report Letter and Measures (Appxs 5a+b)* 
 
 
 
 
 
Xa 
 
 
 
 
 
--- 
Baseline Interviewer-Administered Measures and Chart 
Review (Appx 6)*  
 
 
 
 
 
Xa 
 
 
 
 
 
--- 
Letter to Ineligible Participants (SD 2) 
 
As Needed 
 
 
 
 
 
 
 
--- 
Enrollment Form (Appx 7) 
 
 
 
 
 
 
X 
 
 
 
 
--- 
Randomization Form (Appx 8) 
 
 
 
 
 
 
Xb 
 
 
 
 
--- 
EUC Randomization* 
 
 
 
 
 
 
X 
 
X 
 
 
EUC 
Expectancy Rating Scale and Letter44,45,64 (Appxs 10a+b) 
 
 
 
 
 
 
 
X 
 
 
 
LISC/ 
HISC
Low Intensity Check-In Call Form (Appx 14) 
 
 
 
 
 
 
 
Biweekly 
(wks 2/4/6/8/10/12)
 
LISC 
Upload audio recordings 
 
 
 
 
 
 
 
Biweekly 
(wks 2/4/6/8/10/12)
 
LISC 
Week 7 Mid-Assessment Interviewer-Administered 
Measures (Appx 11)* 
 
 
 
 
 
 
 
 
X 
 
 
All 
Week 13 Self-Report Letter and Measures (Appxs 12a+b)* 
 
 
 
 
 
 
 
 
 
X 
 
All 
Week 13 Interviewer-Administered Measures (Appx 13)* 
 
 
 
 
 
 
 
 
 
Xc 
 
All 
Participant Completion Letter (SD 3)/Resource Sheet (SD 9) 
 
 
 
 
 
 
 
 
 
 
X 
LISC/ 
HISC
Participant Change Status Form (Appx 23) 
 
 
 
 
 
 
 
As Needed 
All 
Adverse Event Form (Appx 22) 
 
As Needed 
 
All 
Crisis Protocol Event Form (Appx 21) 
 
As Needed 
 
All 
Tracking Log (Appx 24) 
 
To be completed for each attempted contact and actual contact 
 
All 
Wake Forest Research Base Responsibility 
EUC Randomization* 
 
 
 
 
 
 
X 
 
 
 
 
EUC 
Investigator adherence rating forms (Appx 18 and 19)* 
 
 
 
 
 
 
 
As needed 
 
LISC/ 
HISC 
Mail Recorder 
 
 
 
 
 
 
As 
needed 
 
 
 
 
LISC/ 
HISC 
Mail CBT Booklet 
 
 
 
 
 
 
X 
 
 
 
 
LISC/ 
HISC 
Mail CBT Booklet 
 
 
 
 
 
 
 
 
 
 
X 
EUC 
Study Therapist Responsibility 
Weekly Therapist activities (Appxs 15-17) recordings* 
 
 
 
 
 
 
 
Weekly (wks 1-13) 
 
HISC 
Tracking log 
 
To be completed for each attempted contact and actual contact 
 
HISC 
Abbreviations: Appx=Appendix, EUC=Enhanced Usual Care, HISC=High-Intensity Stepped-Care Arm, LISC=Low-Intensity Stepped-Care Arm  
* See appendix 26 for details 
a If participant is being seen in person, all of these steps can occur during one appointment 
b Randomization should happen within 30 days of the full screen. If not, full screen (appx 4) will need to be re-administered 
c For participants in the HISC arm, week 13 measures should be completed after the intervention is finished (could be weeks 13-15) 
Note: Regarding potential participant burden, estimated times to complete study measures are as follows: pre-screen (5-10 minutes); screen (up 
to 20 minutes); participant measures at baseline and Week 13 (30-60 minutes); participant measures at Week 7 (5 minutes) 
Note: See the Telehealth website for specific windows of when data should be collected post-randomization for each participant. The PHQ-9 and 
GAD-7 must be entered into the Telehealth website within 48 hours of administration. All other assessments should be entered within 14 days of 
the date assessments are completed unless otherwise specified. 

 
 
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8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION 
 
8.1 
Primary Endpoint 
 
To determine study feasibility, recruitment, accrual, retention, and adherence rates will be calculated as 
follows: 
 
Recruitment. To determine recruitment rate, we will track number of individuals who met all eligibility 
criteria and percent who agree to participate.  
 
Accrual. Accrual rates will be calculated by calculating the mean number of participants recruited per 
month.  
 
Retention. Study retention will be estimated by the proportion of participants who complete the Week 13 
visit. Drop-out is defined as 100% minus the dropout %. 
 
Adherence. Intervention adherence will be estimated as the mean percentage of therapy (high-intensity 
intervention) or check-in (low-intensity intervention) sessions each participant completes. 
 
The Working Alliance Inventory will be summarized with descriptive statistics to describe the therapist-
participant relationship as a process measure 
 
8.2 
Secondary Endpoints 
 
8.2.1. Depression and Anxiety Measures 
 
The PHQ-9 is a self-report measure of DSM-IV symptoms of Major Depressive Disorder.  
Participants rate how often they have experienced nine symptoms over the past 2 weeks on a 
scale of 0 (not at all) to 3 (nearly every day). Responses are summed, with higher scores 
indicating greater depressive symptomatology. It has demonstrated good reliability and validity. 
The traditional cutoff for the PHQ-9 is a score ≥10.  However, ASCO guidelines recommend 
using a score ≥8, based on a study of cancer outpatients76  and a meta-analysis of use of the PHQ-
9 for identifying depression in cancer patients.77  
 
The GAD-753 is a self-report measure of DSM-IV symptoms of GAD.  Participants rate 7 
questions on a scale of 0 (not at all) to 3 (nearly every day); one additional question assesses the 
interference of these symptoms with functioning.  The first 7 questions are summed to create a 
total score.  It has been validated for use in the general population70 and in primary care.53  The 
GAD-7 has demonstrated good sensitivity (89%) and specificity (82%) in identifying GAD 
diagnoses when using a cut point of 10.53 It also has good internal consistency (alphas = 0.89-
0.92) and test-retest reliability (intraclass correlation = .83).53,70  
 
8.2.2. Quality of Life and Symptom Measures: 
 
The Fear of Cancer Recurrence Inventory55 (FCRI; severity subscale) will be used to measure 
self-reported fear of recurrence. This 9-item subscale measures the presence and severity of the 
intrusive thoughts or images associated with the fear of recurrence, and it can be used separately 
as a short form of the 42-item FCRI for the brief screening of fear of cancer recurrence. The 
measure is widely used and has strong reliability and validity (Cronbach’s α=0.75). 
 
The Insomnia Severity Index (ISI)56 is 7-item self-report measure of type and severity of 
insomnia symptoms, including problems with sleep onset, sleep maintenance, or early morning 

 
 
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awakening; satisfaction with current sleep pattern; interference with daily functioning; noticing 
impairment attributed to sleep problems; and level of concern or distress caused by the sleep 
problem.  Responses are summed, with higher scores indicating greater sleep impairment.  It has 
demonstrated reliability and validity in screening primary care patients for insomnia.71 
 
The PROMIS Fatigue Short Form72 is a measure of the experience of fatigue and the impact of 
fatigue on activities across multiple domains.  Seven items are rated on a scale of 1(never) to 5 
(always) based on how often it was experienced over the last 7 days.  
 
The SF-3659 is a self-report measure of quality of life consisting of 36 items that form 8 
subscales:  physical functioning, role limitations due to physical health problems, role limitations 
due to emotional health problems, social functioning, freedom from pain, energy or fatigue, 
emotional well-being, and general health perceptions.  These 8 subscales are also combined into 
two domains: the Physical Component Summary (PCS) and the Mental Component Summary 
(MCS).  All of these scales range from 0 (maximum impairment) to 100 (no impairment). All 
scales range from 0 (maximum impairment) to 100 (no impairment).  It has demonstrated good 
internal validity and construct validity.60,61  
 
The Impact of Events Scale – Revised (IES-R)62,63 is a 22-item self-report measure of cancer-
related distress. It is one of the most widely used measures of event-specific distress. The IES-R 
assesses the frequency with which respondents experience intrusive thoughts, avoidant behaviors, 
and autonomic arousal specific to one’s thoughts and feelings about cancer over the past week. 
 
8.2.3. Health Care Utilization 
 
The Cornell Services Index66 is a structured interview that assesses the frequency of use of 
medical outpatient visits, psychiatric and psychotherapeutic visits, and intensive services such as 
hospitalizations, emergency room visits, and home health visits.  The services assessed in the 
Cornell Services Index are aggregated into outpatient psychiatric or psychological services, 
outpatient medical services, professional support services, and intensive services.   
 
8.2.4. Implementation Costs 
 
Tracking logs will measure the time spent in intervention-related activities such as bi-weekly 
check-in phone calls and therapy sessions with participants in stepped care, related to 
implementation. Tracking logs should be entered within 1-2 days of intervention-related 
activities; however, sites have up to 30 days to enter this information. NCORP Research Base 
Staff will keep an internal record of staff meetings, phone charges, mailing and printing costs and 
therapist training.   
 
8.3 
Off-Study Criteria 
 
Participants may go ‘off-study’ for the following reasons: the protocol intervention and any protocol-
required follow-up period is completed, serious adverse event, lost to follow-up, withdraw consent, PI 
removes from study, or death. 
 
For subjects who are enrolled, site staff must contact the subject at the next study visit with at least 5 
attempts.  After 5 documented contact attempts the subject will be considered lost to follow-up.  Site staff 
must complete a Participant Status Change Form (Appendix 23) in the Telehealth website. 
 
8.4 
Study Termination 
 
NCI/DCCPS as the study sponsor or the Wake Forest NCORP Research Base has the right to discontinue 
the study at any time.  

 
 
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9. 
CORRELATIVE/SPECIAL STUDIES- N/A 
 
10. 
SPECIMEN MANAGEMENT- N/A 
 
11. 
REPORTING ADVERSE AND SERIOUS ADVERSE EVENTS 
 
11.1 
Reportable Adverse Events 
 
An adverse event (AE) is defined as any untoward or unfavorable medical occurrence in a human subject, 
including any clinically significant abnormal sign (for example, abnormal physical exam or laboratory 
finding), symptom, or disease, temporally associated with the subject’s participation in the research, 
whether or not considered related to the subject’s participation in the research. The burden of collecting 
and reporting data on every possible AE is excessive and therefore, in Telehealth, sites will report all 
serious adverse events (SAEs) described in Section 11.2 and selected AEs listed in Section 11.3.  
 
SAEs and AEs will be ascertained by site staff for all participants at Weeks 7 and 13. Telehealth staff will 
administer the Adverse Event Ascertainment Form (Appendix 22) to specifically query participants about 
safety events at weeks 7 and 13.   In addition, adverse events may also be reported to study staff 
spontaneously through telephone calls, emails or other correspondence.  In addition to local reporting 
requirements, all SAEs and selected AEs will be recorded on the Adverse Event Form by clinic staff.  
SAEs occurring during the study should also be reported for all participants to CTEP-AERS (see section 
below).  
 
AEs will be assessed according to the grade associated with the CTCAE term. AEs that do not have a 
corresponding CTCAE term will be assessed according to the general guidelines for grading used in the 
CTCAE v5.0.. A copy of the CTCAE can be found at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
11.2  
Serious Adverse Events 
 
Definition: Regulations at 21 CFR §312.32 (revised April 1, 2014) define an SAE as any untoward 
medical occurrence that at any dose or intervention level has one or more of the following outcomes: 
 
A Serious Adverse Event (SAEs) is defined if it results in ANY of the following outcomes: 
 Death 
 Life-threatening  
 Results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24hours 
 A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
 A congenital anomaly/birth defect 
 Important Medical Event (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
Reporting Requirements for above Study Descriptions: 
 All unexpected hospitalizations regardless of grade 
 All Grade 5 toxicities (deaths-expected and unexpected) 
 All unexpected Grade 4 toxicities 
 All additional reporting requirements as outlined in the protocol 

 
 
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Serious adverse events as described above must be reported on the Telehealth Adverse Event Form and 
also be reported to CTEP-AERS: 
 
CTEP-AERS (Research Base Data Management) reporting timelines are defined as: 
 Deaths or life threatening events (Grades 4-5): 24-Hour; 5 Calendar Days - The SAE must 
initially be reported via CTEP-AERS within 24 hours of learning of the SAE, followed by a 
complete expedited report within 5 calendar days of the initial 24-hour report. 
 Hospitalizations, disabling, important medical events (IME) that may not result in death, be 
life threatening, or require hospitalization (Grade3) and study specific adverse events:  10 
Calendar Days - A complete expedited report on the SAE must be submitted within 10 
calendar days of learning of the SAE. 
 
11.3 
Selected Adverse Events 
 
A select list of adverse events include suicide attempts, psychosis, worsening anxiety, worsening 
depression, and suicidal ideation, should be reported as an adverse event, regardless of whether they 
resulted in an ER visit or hospitalization.  
 
11.3.1. Definition of Worsening Anxiety or Depression 
 
An adverse event form should be completed for any participant who indicates a significant 
worsening in anxiety or depression scores (1 standard deviation increase (rounded to the nearest 
integer) on the GAD-7 (Change≥4)75 or PHQ-9 (Change≥6)73,74,51 from baseline). The computer 
software system will automatically generate an e-mail to the co-PIs and the project manager. If 
there is a need for immediate treatment (e.g., active suicidal ideation, active psychotic symptoms, 
disorientation, and active substance abuse) at any point in time, staff persons will notify the co-
PIs.  In both cases, the participant may be referred for psychiatric care.   
 
12. 
STUDY MONITORING 
 
12.1 
Data Management 
 
The Enrollment Form should be completed on-line  at randomization.  Data will be entered 
directly into the study website.  The PHQ-9 and GAD-7 must be entered into the Telehealth 
website within 48 hours of being administered.  The Crisis Protocol form (Appendix 21) must be 
entered into the Telehealth website at the time the form is completed with the participant.  Refer to 
Section 11 for submitting the Adverse Event form.  All other assessments must be completed 
within the designated study visit windows then data entered into the Telehealth website by 
designated site staff or designated study therapist within 14 days from the date assessments are 
completed.   
 
12.2 
Case Report Forms 
 
Participant data will be collected using protocol-specific case report forms (CRF).  
 
12.3 
Source Documents 
 
The sources of research material will include information provided through participant interviews, 
intervention sessions, and self-report questionnaires specifically for this research study. A number of 
steps will be taken to ensure the confidentiality of research data collected during the study. The study will 
obtain a Certificate of Confidentiality which prevents researchers from being forced to disclose 
identifying information by certain legal proceedings. All forms will be stored in locked file cabinets. 

 
 
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Names will be removed from all forms and records and replaced with participant numbers. Recorded 
sessions will be erased upon completion of data collection. Information stored in the computer will be 
password protected. Only members of the investigative team will have access to any participant 
information and data. The identities of participants will not be revealed in publications and presentations 
of any results from this project. Procedures specified in the consent form are consistent with HIPAA 
regulations. All investigators have completed NIH-required training in human subjects protection. 
 
An investigator and other designated staff are required to prepare and maintain adequate and accurate 
documentation that records all observations and other data pertinent to the investigation for each 
individual participating in the study. All data recorded in the research record (including data recorded on 
CRFs) must originate in the participant’s medical record, study record, or other official document sources. 
 
Source documents substantiate CRF information. All participant case records (e.g., flow sheets, clinical 
records, physician notes, correspondence) must adhere to the following standards: 
 
 Clearly labeled in accordance with HIPAA practices so that they can be associated with a 
particular participant identification number (PID); 
 Legibly written in ink; 
 Signed and dated in a real time basis by health care practitioner evaluating or treating the 
participant; and 
 Correction liquid or tape must not be used in source documents or on CRFs. 
 Corrections are made by drawing a single line through the error. Do not obliterate the original 
entry. Insert the correct information, initial, and date the entry. 
 
12.4 
Data and Safety Monitoring Plan 
 
The Comprehensive Cancer Center Data Safety Monitoring Board meets every six months to review all 
phase II and phase III protocols. The Board includes members demonstrating experience and expertise in 
oncology, biological sciences, biostatistics, pastoral care/counseling, and ethics. The members of this 
committee as well as the organization statistician will oversee the safety monitoring of the study, ensure 
that the privacy of all participants in the study is protected and ensure that participants' interests are 
primary, that is, above the interests of the scientific investigation. Adverse events will be elicited by study 
staff during assessments and check-in calls for the EUC group and by the study therapists during each 
session. Information about any adverse events will be presented. By examining this information, the data 
and safety monitoring team will keep abreast of critical issues regarding recruitment and data integrity. 
Reports of all DSMB meetings and recommendations will be provided to the NCI and WFUSM IRB. 
 
12.5 
Sponsor or FDA Monitoring 
 
The NCI, DCCPS (or their designee)  may audit various aspects of the study. This auditor will be given 
access to facilities, databases, supplies and records to review and verify data pertinent to the study. This 
protocol does not include pharmaceuticals or require FDA monitoring.  
 
12.6 
Record Retention 
 
Clinical records for all participants, including CRFs, all source documentation (containing evidence to 
study eligibility, history and physical findings, laboratory data, results of consultations, etc.), as well as 
IRB records and other regulatory documentation will be retained by the Investigator in a secure storage 
facility in compliance with Health Insurance Portability and Accountability Act (HIPAA), Office of 
Human Research Protections (OHRP), Food and Drug Administration (FDA) regulations and guidances, 
and NCI/DCCPS requirements, unless the standard at the site is more stringent. The records for all studies 
performed under an IND will be maintained, at a minimum, for two years after the approval of a New 
Drug Application (NDA). For NCI/DCCPS, records will be retained for at least three years after the 

 
 
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completion of the research. NCI will be notified prior to the planned destruction of any materials. The 
records should be accessible for inspection and copying by authorized persons of the Food and Drug 
Administration. If the study is done outside of the United States, applicable regulatory requirements for 
the specific country participating in the study also apply. 
 
 
 
13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Description 
 
13.1.1. Primary Objectives  
 
To determine feasibility (recruitment, accrual, retention, adherence) of a RCT of a stepped-care 
telehealth mental health intervention (tailored to symptom level) versus enhanced usual care in 90 
post-treatment cancer survivors with moderate or severe levels of emotional distress (anxiety 
and/or depressive symptoms). 
 
13.1.2. Secondary Objectives  
 
To obtain preliminary data on the efficacy and variability of a stepped-care telehealth mental 
health intervention (tailored to symptom level) versus enhanced usual care for reducing emotional 
distress (anxiety and/or depressive symptoms) in 90 post-treatment cancer survivors. 
 
To obtain preliminary data on the efficacy and variability of a stepped-care telehealth mental 
health intervention (tailored to symptom level) versus enhanced usual care for secondary 
outcomes (sleep disturbance, fatigue, fear of recurrence, cancer-related distress, and QOL) in 90 
post-treatment cancer survivors. 
 
To determine costs associated with both stepped-care telehealth and enhanced usual care 
interventions from the perspective of a healthcare provider. We will determine costs of 
intervention implementation and health care utilization in all arms over the course of the 
interventions. 
 
13.1.3. Exploratory Objectives  
 
To examine potential differential effects of the intervention on anxiety, depression, sleep 
disturbance, fatigue, fear of recurrence, and QOL, by gender, age, race/ethnicity, stratification 
arm (moderate, severe), and psychotropic medication use at baseline. 
 
To examine mediating effects of expectancy ratings of the intervention on anxiety and 
depression. 
 
13.2 
Randomization/Stratification  
 
Participants will be stratified by baseline score ≥15 on the GAD-7 and/or on the PHQ-9, indicating severe 
anxiety or depressive symptoms, and by whether they qualified for the study by the GAD-7, PHQ-9, or 
both. Participants with moderate symptoms only (8-14 on the PHQ-9 and <15 on the GAD-7 or 10-14 on 
the GAD-7 and <15 on the PHQ-9) will be randomized to either the low-intensity stepped-care telehealth 
or to the enhanced usual care (EUC control) with equal probability. Participants with severe symptoms 
will be randomized to either the high-intensity stepped-care telehealth intervention or the EUC control 
with equal probability. Participants randomized to the low-intensity stepped care telehealth arm who 
experience increased symptoms at week seven and now experience severe level of symptomatology will 
receive the high-intensity intervention (see Section 7.1). Analysis will proceed as intent-to-treat using 

 
 
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their initial stepped-care telehealth assignment; we do not anticipate that many people will change from 
moderate to severe during the study. We anticipate enrolling 45 patients in the stepped-care telehealth 
intervention and 45 in the enhanced usual care group. We will enroll 50 participants in the moderate 
symptom strata, and 40 participants in the severe symptom strata. Block sizes will be chosen randomly to 
ensure that future assignments cannot be inferred from previous ones. 
 
13.3 
Sample Size 
 
The sample size (N=90) is based on goals of estimating retention, recruitment, adherence and accrual 
rates and effect sizes to inform design of a larger efficacy trial. If the drop-out rate is >30%, a larger study 
may not be feasible. With N=90, we are confident that this rate will be 30% when the observed drop-out 
rate is as large as 22% (upper limit of the one-sided 95% CI is 29.2%). Similarly, the lower limit of a one-
sided 95% confidence interval for the recruitment rate can be estimated within 8.2% of the observed rate 
if we approach at least 100 participants to recruit 90, and the lower limit of a one-sided 95% confidence 
interval for the adherence can be estimated within 8.7% of the observed rate with N=90. Using the normal 
approximation to the Poisson, we can estimate the lower limit of the one-sided 95% confidence interval of 
the accrual rate within approximately 2 people per month if the observed rate is 11 people per month. To 
compare differences between the groups on changes in the PHQ-9 and GAD-7 scores, we can estimate the 
intervention effect within 0.46 SD with a sample size of 36/group (stepped-care telehealth, enhanced 
usual care), allowing 20% dropout of the 45/group randomized. This corresponds to 2.7 points on PHQ-9 
and 1.9 points on GAD-7 using SDs from studies of change in the measures of 5.8 and 4.2 points, 
respectively.51,73–75   
 
13.4 
Primary Objective, Endpoint(s), Analysis Plan 
 
For Objective 1.1.1, recruitment, accrual, retention, and adherence rates will be calculated. To determine 
the recruitment rate, we will track number of eligible participants and percent who agree to participate. 
Accrual rates will be calculated by calculating the mean number of participants recruited per month. 
Study retention will be estimated by the proportion of participants who complete the Week 7 and 13 
visits. Intervention adherence will be estimated as the mean percentage of therapy or check-in sessions 
each participant completes. Drop-out is defined as 100% minus the dropout %. 95% confidence intervals 
will be calculated for each measure to quantify uncertainty in the estimates and to determine if the lower 
(recruitment, accrual) or upper (retention, adherence) limit would indicate lack of feasibility for future 
work.  
 
13.5 
Secondary Objectives, Endpoints, Analysis Plans 
 
For Objective 1.2.1, baseline descriptive statistics will be compared by intervention arm using chi-square 
tests for categorical variables and ANOVA for continuous variables. Due to randomization, we do not 
anticipate differences by intervention arm; if they are found, we will adjust for them in the analyses for 
Objectives 1.2.1, 1.2.2, 1.2.3, and 1.2.4. The Working Alliance Inventory will be summarized using 
descriptive statistics.   
 
Depression and anxiety outcomes (PHQ-9 and GAD-7) will be analyzed using mixed-model analysis of 
covariance (ANCOVA) to account for intra-individual correlations among longitudinal measures. The 
model will contain terms for the intervention group, baseline value of the outcome, therapist or site staff 
person completing check-in calls, psychotropic medications use, a time effect (mid-, post-intervention), 
and the time by intervention interaction term (to test whether the intervention effects vary by time). 
Because participants may exhibit moderate or severe levels of either depression or anxiety, we will create 
a combined variable that indicates if a participant had moderate/severe depression or anxiety at mid- or 
post-intervention. Each stepped-care telehealth group will be compared with EUC using a GEE approach 
with a logit link to determine if rates of the combined outcome differ at mid- or post-intervention. Other 
outcome measures (sleep disturbance, fatigue, fear of recurrence, cancer-related distress, and quality of 
life) will be analyzed using ANCOVA at week 13 to meet objective 1.2.2.  

 
 
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For Objective 1.2.3, we will calculate total cost of the stepped-care telehealth (low intensity, high 
intensity) and the EUC interventions and average cost/survivor screened and randomized to each trial 
arm. Total cost includes costs of intervention implementation and health care costs for each participant.  
 
Implementation costs will be determined using data on time spent on intervention activities reported in 
the tracking logs. Time spent on the intervention includes i) training personnel to screen and deliver the 
intervention including time of trainer and trainees; ii) time spent by interventionists on intervention 
activities, including screening, scheduling and delivering the phone sessions, and documenting 
contacts/progress; iii) phone charges; and iv) other supply costs (e.g., CBT workbooks). Cost of time will 
be valued using wage rates based on national averages for research staff and psychotherapists. Other costs 
(e.g., telephone charges and printed materials) will be valued using project records on expenses incurred. 
We will sum all costs related to each intervention to obtain the total cost of implementing each. Total 
costs in each study arm will be dividing by the number of patients served to obtain the average cost per 
patient. Sensitivity analyses will be conducted to assess how implementation costs vary depending on the 
inputs used, such as the salaries of interventionists or supervisors.  
 
Health care cost will be determined using data from self-reported utilization of heath care services 
(Cornell Services Index).66 To calculate the costs related to these health care events, we will use published 
data on average costs of these events or data from sources such as the Medicare Fee Schedule and/or the 
Medical Expenditure Panel Survey. We will conduct analyses to examine the impact of the stepped-care 
interventions on health care utilization and costs: similar to analyses specified above for Objective 1.2.1, 
we will use linear models with utilization or costs as the dependent variable, and the arm assignment as 
the independent variable. Because the distribution of costs is usually skewed, we will consider using a 
generalized linear model with a gamma link. 
 
13.6 
Exploratory Objectives, Endpoints, Analysis Plans 
 
We will perform stratified subgroup analysis of the outcomes in Objectives 1.2.1 and 1.2.2. by gender, 
age, race/ethnicity, stratification arm (moderate, severe), and psychotropic medication use at baseline to 
meet Objective 1.3.1 using ANCOVA at week 13.  To analyze Objective 1.3.2, we will use a mediation 
approach to examine whether expectancy ratings mediate the relationship between the intervention and 
the outcomes of interest (PHQ-9, GAD-7, or the combined outcome) at the intervention mid-point or end.  
First, we will examine whether the expectancy rating score is  a significant predictor of the outcome in the 
mixed-model analysis of covariance (ANCOVA) model with terms for the expectancy rating score, 
baseline value of the outcome, therapist or site staff person conducting check-in calls, psychotropic 
medications use, a time effect (mid-, post-intervention), and the time by intervention expectancy score 
term (to test whether the expectancy score effects vary by time).  Then we will fit the same model with 
the intervention effect, expectancy rating score, and their interactions with each other and time. If the 
effect for the mediator is significant in this model and the parameter estimate of the intervention effect is 
smaller than in the analysis of Objective 1.2.1 it will indicate evidence of mediation. 
 
13.7 
Reporting and Exclusions 
 
Unless we receive written or verbal withdrawal of consent, we will try to reach every participant for 
telephone calls, telephone sessions, and assessments as outlined in the protocol. 
 
The dataset used in the analysis of Objective 1.1.1 will include all eligible participants to calculate 
recruitment rates. Accrual, retention, and adherence will be calculated on the participants who consent to 
participate in the study.  The analysis of the secondary objectives and exploratory objective will include 
all participants who consent to participate in the study. The ANOVA models used for the secondary 
objectives use data from all available time points and allows for data to be missing at random. For the 
analyses of the secondary objectives and the exploratory objective, we will use an intent-to-treat 
approach. If participants are moved from low intensity to high intensity they will be analyzed using the 

 
 
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low intensity assignment (intent to treat). In exploratory models, we will analyze the impact of adherence 
by including it as a predictor. 
 
13.8 
Evaluation of Response 
 
All participants in the study who complete the PHQ-9 and GAD-7 at Week 13 will be evaluable for 
response to the intervention.  In sensitivity analyses, we will evaluate how imputation of these values 
utilizing either baseline or Week 7 data impact study conclusions. Note that this is a feasibility study and 
analyses of the intervention effects will be used to plan future studies, not to demonstrate efficacy. 
 
 
 

 
 
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