Post-chemotherapy Symptom Management: Testing Intervention Sequences in a SMART Design
Phase: NA
Conditions: Cancer
Sponsor: University of Arizona

 
 
 
 
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SCIENTIFIC REVIEW COMMITTEE 
 
Title: 
Post-Chemotherapy Symptom Management: Testing Intervention Sequences in a SMART 
Design NCT03494166 
 
KEY PERSONNEL  
 
Name 
Organization 
Role on Project 
Terry Badger, PhD 
University of Arizona 
Principal Investigator  
 
Alla Sikorskii, PhD 
Michigan State University 
Principal Investigator  
 
Chris Segrin, PhD 
University of Arizona 
Co-Investigator 
 
 
Tracy Crane, PhD 
University of Arizona 
C-Investigator 
Pavani Chalasani, MD, MPH 
University of Arizona 
Co-Investigator 
 
  
Charles Given, PhD 
Michigan State University 
Consultant 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INDEX  
 
 
 
 
 
 
Section 
Schema/Study Flowchart 
Background & Rationale 
1.0 
Objectives/Specific Aims 
2.0 
Sample Eligibility Criteria 
3.0 
Participant Registration 
4.0 
Research Design, Methods and Procedures 
5.0 
Measures/Data Collection Instruments 
6.0 
Detailed Description of Intervention 
7.0 
Statistical Considerations 
8.0 
Study Timeline 
9.0 
Data Safety and Monitoring Plan 
10.0 
Reporting Adverse Events 
11.0 
Patient Consent and Peer Judgment 
12.0 
References 
13.0 
Appendices: 
14.0 
 
 
 

 
 
 
 
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SCHEMA OR FLOWCHART 
Insert schematic or diagram outlining study design and procedures 
 
 

 
 
 
 
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1.0 
BACKGROUND & RATIONALE 
 
Scientific background and basis for hypothesis(es) to be tested. Include justification for 
conducting study and results of similar studies or pilot data.   
 
Nearly 15.5 million Americans have survived cancer and virtually all have experienced symptoms from 
cancer treatment that negatively impact their quality of life.1 Although numerous symptom management 
interventions have been tested during active cancer treatment,2-5 few have addressed the continuing 
fatigue, pain, depression, anxiety, insomnia, and other symptoms that endure following the end of 
treatment.6-10 Existing post-treatment symptom management research has targeted survivors several 
months after the end of active treatment, overlooking the immediate post-treatment period. During this 
period, some survivors have their symptoms resolve naturally with low need for interventions, while 
others suffer from high symptom burden, with about 30% experiencing depression.11-13 Even when 
depressive symptoms are not sufficiently severe to warrant a clinical diagnosis of depression,14-17 they 
need attention to decrease morbidity and mortality.18-20  
 
Based on the work of this team 21-23 and others,24-27 the number, severity and persistence of symptoms 
following chemotherapy for solid tumors can be predicted in part by comorbid conditions and depressive 
symptoms. Both of these easily identifiable factors influence the time needed to recover from cancer 
treatment,28-30 and are associated with multiple symptoms.31-36 Thus, we propose to target survivors with 
one or more comorbid conditions and elevated depressive symptomatology who are at risk for lingering 
symptoms that require interventions following at the end of chemotherapy; we call these “high need” 
survivors in this application. In our previous studies, 65% of survivors of solid tumors met these criteria 
and had higher persistent symptom burden than did survivors without these co-morbidities.21-23,37 
 
Our scientific premise is that depression, prevalent at the end of chemotherapy, is an important cognitive 
and emotional barrier for self-management of symptoms. Building on this premise, we seek to determine 
if addressing depressive symptoms will allow survivors to reframe their beliefs regarding the efficacy of 
their actions towards managing their symptoms. The goal of this research is to determine the best 
sequencing of interventions for high need survivors using a sequential multiple assignment randomized 
trial (SMART) design (Figure 1). Two interventions with proven efficacy 4,37-39 will be used: 1) a 
minimal intervention, the printed Symptom Management and Survivorship Handbook (SMSH) with 
evidence-based self-care strategies for elevated symptoms and 2) a more intensive intervention that 
combines SMSH with a Telephone Interpersonal Counseling (TIP-C) intervention for managing 
depressive symptoms.39,40 We follow the clinical logic of starting with SMSH, assessing its success in 
managing depressive symptoms (response), and continuing it when effective. If SMSH proves 
inadequate after 4 weeks for a survivor, we will test adding a more intensive TIP-C. 
 
 
2.0 
OBJECTIVE(S)/SPECIFIC AIMS 
 
Purpose and specific aims of the study. 
 
The proposed SMART will enroll an ethnically diverse (about 30% Hispanic) sample of N=344 (post-
attrition) survivors of solid tumors at the end of chemotherapy. As in past work,
41-43 we will deliver the 
interventions in either English or Spanish, based on the participant’s preference. The specific aims are 
to: 
 

 
 
 
 
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Aim 1. Test the effects of interventions on the summed index of severity of 15 post-chemotherapy 
symptoms (primary outcome) and symptom-specific responses and times to response (secondary 
outcomes). 
Hypothesis 1. Survivors in the group that starts with TIP-C+SMSH versus to the group that starts with 
SMSH alone created by the first randomization will have better primary and secondary outcomes at 
weeks 1-13. 
Hypothesis 2. Among non-responders to the SMSH alone after 4 weeks, survivors in TIP-C+SMSH as 
compared to the SMSH alone group created by the second randomization will have better primary and 
secondary outcomes at weeks 5-13. 
Hypothesis 3. Self-efficacy and social support will mediate improvements in the primary outcome at 
week 13. 
Aim 2. Compare symptom outcomes of intervention sequences against the benchmark low need group. 
Exploratory Aim. Explore which survivor characteristics are associated with responses to the SMSH 
alone during weeks 1-4 and optimal symptom outcomes during weeks 1-13. This will allow us to 
determine tailoring variables to inform decision rules for choosing intervention sequences for individual 
survivors in the future. 
 
The SMART design provides a state-of-the-art framework for rigorous testing of this innovative 
symptom management approach in the overlooked immediate post-chemotherapy period.  
 
 
3.0 
SAMPLE ELIGIBILITY CRITERIA 
 
Specific inclusion/exclusion requirements which must be met for entry.   
 
Inclusion criteria include: (1)18 years of age or older, 2) have access to a telephone, 3) understand 
English or Spanish, and 4) are not currently receiving counseling and/or psychotherapy. Survivors must: 
5) have a new diagnosis or localized recurrence of solid tumor cancer, and 6) be finishing curative intent 
adjuvant chemotherapy or chemoradiation, and do not have any subsequent cancer treatments planned, 
except for radiation therapy, hormonal therapy or trastuzumab for breast cancer. 
 
Exclusion criteria include: (1) diagnosis of a psychotic disorder in medical record verified by the 
recruiter; 2) nursing home resident; 3) bedridden; 4) currently receiving counseling and/or 
psychotherapy. For instance, the sample will include survivors finishing chemoradiation for stage III 
lung cancer, survivors of breast, colon, rectal, resected pancreatic or resected lung cancer.  
 
4.0 
PARTICIPANT RECRUITMENT/ENROLLMENT 
 
Describe how study participants are to be recruited and enrolled in the study with appropriate 
contact phone numbers, etc. Stratification factors, participant characteristics which are 
balanced across treatment arms or used to determine intervention doses are described here.  
The randomization scheme is included here if applicable. 
 
Recruitment and enrollment. The proposed SMART will enroll an ethnically diverse (about 30% 
Hispanic) sample of N=344 (post-attrition) survivors of solid tumors at the end of chemotherapy.  
 
Survivors are recruited at the University of Arizona Cancer Center (UACC) locations in Tucson and 
Phoenix, Valleywise Health in Phoenix, and in the community. Recruiters (nurses or other health 
professionals) have research roles and do not provide direct care at the participating oncology settings. 
Survivors will be assured of the confidentiality of all information provided and that refusing to 
participate will not alter their health care. Survivors will continue to receive standard medical and 
nursing care, so they may seek care from their health providers for any health problems that arise. For 

 
 
 
 
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those who refuse, the recruiter will ask their reason for refusal. For those who agree to participate, the 
recruiter will obtain the consent form, confirm treatment plan, and complete the recruitment form that 
includes name, main and alternative contact information, convenient call time, cancer site and stage, 
names and contact information for oncologist and primary care physician. Study participants will be 
informed that they will be 1) randomization to SMSH or TIP-C+SMH and may be re-randomized after 4 
weeks to either continue with the SMSH alone or to add TIP-C, 2) telephone symptom assessment and 
intervention sessions are weekly, and 3) there is no cost to study participation. Further, 4) the study lasts 
13 weeks to include all data collection, 5) Interventions are designed to help reduce symptoms, 6) A 
review of potential risks/benefits; and 7) there are study incentives. 
 
Using the inclusion/exclusion requirements detailed in section 3.0, the sample will include survivors 
finishing chemoradiation for stage III lung cancer, survivors of breast, colon, rectal, resected pancreatic 
or resected lung cancer. Because site of cancer and treatment type are balancing factors in 
randomizations, these variables will be equally distributed among trial arms. Our prior research indicates 
that participation in counseling and/or psychotherapy is rare. This exclusion criterion will not 
substantially limit the population but will eliminate potential confounding of the intervention effects 
with extraneous influences. Based on the demographic characteristics of the AZ population, the sample 
will consist of approximately 60% non-Hispanic white, 30% Hispanic/Latino, 3% each African 
American and Asian American, and 4% American Indian participants. There is an ample pool of cancer 
survivors available to meet enrollment targets. In 2017, Arizona is estimated to have 35,810 newly 
diagnosed cases of cancer,1 of these the majority are solid tumors. Conservatively, we will have access 
to about 10%, of which approximately 1/3rd or 1000 will satisfy the inclusion criteria. If 1/3rd of these, 
or 330, are approached and half will consent to participate, we can recruit over 160 survivors per year. 
Given this team’s past successful recruitment at the UACC and community sites (see letters of support), 
the proposed study will easily meet the goal of 145 survivors per each of 3 years of recruitment. 
 
Sample Size and power considerations. To determine sample size, we started at the right of the 
schematic in Figure 1 (the second randomization) and moved from right to left to determine the number 
of survivors needed. To power the comparisons of groups created by the second randomization 
(Hypothesis 2), we used the effect size of Cohen’s d=0.39 (adjusted for baseline), the smallest seen in 
the preliminary data for TIP-C against an educational intervention (Table 2) to conservatively estimate 
sample size requirements. We further adjusted this effect size for the reduction in error variance due to 9 
repeated measures of the primary outcome. In past studies, Pearson correlation coefficients between 
pairs of repeated measures of summed symptom severity index ranged from r=0.36 to 0.77, resulting in 
the range of the adjusted effect sizes from d=0.54 to 0.84. Using the smallest adjusted d=0.54, the 
required sample size is 60 per group created by the second randomization, for power of .80 or greater in 
two-tailed tests at the 0.05 level of significance. For the analysis of symptom response, the unit of 
analysis will be participant-symptom. Based on the preliminary data and inclusion criteria, 120 
participants from the second randomization are expected to average 2.7 symptoms at moderate or severe 
levels, yielding 324 symptom cases treated as nested within participants as described in the analysis. 
After accounting for nesting of the symptom cases within survivors, the adjusted sample size for the 
analysis of symptom response is 248 symptom cases, or 124 per group. Examples of detectable 
differences include symptom response of 47% versus 30%, rates consistent with past studies.139,152 
Proceeding further from left to right in Figure 1, 120 dyads from two groups created by the second 
randomization will be non-responders on depression to the SMSG alone after 4 weeks. From past work, 
the response rate to the SMSG on depression was 30%,97 therefore 120 non-responders will be 70% of 
172 randomized to the SMSG alone in the first randomization. The comparison of 172 to 52 participants 
allocated to the TIP-C+SMSG in the first randomization will have power of 0.92 to detect the effect size 
of 0.54 (adjusted for the repeated measures) in testing the hypotheses associated with Hypothesis 1. The 
tests of mediation effects (Hypothesis 3) will have an even greater power than the comparisons of 

 
 
 
 
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randomized arms because of further reduction in error variance. Formal power considerations are not 
applicable for the exploratory aim. Therefore, the post-attrition size of the high need group is N=224. 
Since this group is 65% of the survivors finishing chemotherapy, we will screen 344, leaving 120 in the 
benchmark low need group. To account for 20% attrition based on past work, we will need to have 430 
survivors’ consent. 
 
Subject incentives. Incentive payments not only significantly improve recruitment rates
165, but there are 
no significant differences in key dependent variables for those offered versus those not offered an 
incentive.
166 Provision of incentives equivalent to the demands of participation is vital to successfully 
recruiting minorities into research and getting a culturally representative diverse sample.
167-170 After 
every interview, participants will receive thank you letters and gift cards from a large retail merchant in 
graduated amounts ($40 after baseline and $50 after week 13). The total compensation will be $90 for 
about 6-7 hours of participants’ time over 13 weeks in the high need group, or 2 hours in the low need 
group. 
 
Strategies to minimize attrition. 1) Recruiters will emphasize the importance of participating in the 
entire study. 2) Survivors will be asked to mark their calendars for study calls. 3) E-mail or text 
reminders are sent about upcoming telephone contacts if agreed to by participants. 4) Weekly calls 
will maintain contact for the entire study duration. 5) Graduated compensation is provided for 
assessment sessions. These strategies have worked well in the past, with retention rates of ≥75%. 
 
Community ties and cultural sensitivity.  We use experienced staff members with extensive ties to 
the local survivorship communities. The study brochures will be developed in English and in Spanish 
with community advisors.39,40 Seven principles of language competence, cultural competence, ethical 
conduct, mission or purpose, empathy, graciousness and credibility171 will be incorporated in all 
interactions. We will show cultural sensitivity along two dimensions.172,173 Surface structure involves 
matching messages to observable ‘superficial’ characteristics of the target population (e.g., speaking 
English or Spanish). Deep structures involve incorporating some of the socio-cultural, historical, 
environmental and psychological forces that influence health behaviors. For example, we will 
incorporate the value of personalismo by talking about participants’ lives at the beginning of 
sessions. Participants from past studies have appreciated the flexibility and respect (respeto). 174 
These techniques allow us to personalize our interactions, addressing both personal and cancer issues 
of concern. This approach is critical to gain trust (confianza). 
 
Management of post-chemotherapy symptoms: high versus low need. Breast cancer has been the 
focus of the few intervention studies designed to support patients as they finish chemotherapy.6,7,72,73 
Post- treatment interventions produced modest benefits for fatigue,6,7 72,74 other symptoms,75,76 or 
overall quality of life.61,77 The modest effects observed may be due, in part, to directing interventions 
toward those who may not need them along with those who do, creating a floor effect for symptom 
reductions and diluting the improvements realized among those in the high need subset. This 
application addresses these problems by separating out a group with low need for symptom 
management and intervening with only a predefined high need group in an ethnically diverse (at least 
30% Hispanic) sample of survivors of solid tumors. Survivors will be stratified according to the need 
for management of post-chemotherapy symptoms with two identifiable factors (comorbid conditions 
and depressive symptoms). The first factor, comorbidity, negatively affects the health status prior to 
the cancer diagnosis.78 During cancer treatment, chemotherapy exacerbates comorbidity- related 
impairments in health status.79-84 Comorbid conditions as important predictors of treatment85 and 
treatment outcomes,79-84,86-94 may influence the time needed to recover from cancer treatment,28,29 and 
are associated with multiple symptoms.79,82 As for the second factor, there is strong evidence that 

 
 
 
 
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depressive symptoms influence severity of other symptoms, and extend recovery from 
treatment.60,80,95 Although many survivors suffer from depressive symptoms that are not sufficiently 
severe to warrant a clinical diagnosis of depression,14-17 these symptoms need attention and are highly 
treatable.18,20  
 
 
Based on this body of literature, comorbidity and depressive symptoms will determine the need for 
postchemotherapy symptom management. The use of these factors for the need determination is further 
supported by our past work with survivors during chemotherapy, in which we followed a subset of 
N=143 into the postchemotherapy period (Table 1 for 5 most prevalent symptoms).21,22 Survivors with at 
least one comorbid condition and a Center for Epidemiologic Studies- Depression (CES-D) score of ≥16 
(the established clinical cut point)96 at the end of chemotherapy (high need) had higher persisting 
symptom burden compared to patients with no comorbid conditions or CES-D score < 16 (low need). 
Moderate or severe fatigue, pain, weakness, distress, dyspnea, and insomnia, as defined by previously 
established validated cut-points,97 persisted in over 20% of high need survivors for at least 8 weeks post-
chemotherapy. Survivors in the high need group experienced on average 2.7 moderate or severe 
symptoms at 2 weeks post chemotherapy, and 2.3 at 8 weeks. In contrast, the prevalence of residual 
symptoms in the low need group was lower at week 2. If it was higher (e.g., insomnia), it declined 
without interventions at week 8. The mean number of symptoms in the low need group was 1.6 at week 
2, and 1.1 at week 8 post-chemotherapy. Among survivors with one or more comorbid condition, those 
with CES-D scores ≥ 16 did not differ on severity of depression with respect to specific comorbidities. 
These findings are consistent with a review of 34 studies,98 where the number but not specific 
combinations of comorbid conditions were related to the outcomes of chemotherapy. Thus, the strata we 
propose are robust and not influenced by specific comorbid conditions. The proposed work builds on 
this highly significant evidence to conserve resources by targeting only a group of survivors with high 
need for symptom management interventions. 
 
The low need survivors will not receive interventions but will be followed up over time to confirm 
that they are experiencing a natural resolution of symptoms following the end of chemotherapy. 
Their symptom outcomes are benchmarked against those produced by the intervention sequences. 
For example, while symptom severity may be lowered by the intervention in the high need group, 
would severity be at the same level as in the benchmark group? Because the low need group is 
created using stratification and not randomizations, the conclusions from the comparison to high need 
patients will not be causal. Instead, this comparison will allow us to gauge the clinical significance of 
the results and their relevance to survivors 
Hispanic/Latino Survivors. Given the increasing population of Hispanic cancer survivors, providing 
and testing an intervention in the participant’s primary language could have national significance. In our 
past work with non-Hispanic samples, 65% were in the high need group,21,22 and this percentage may be 

 
 
 
 
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larger among Hispanic survivors who have a higher prevalence of depression and comorbidity compared 
to non-Hispanic whites. 99,100 101-104 In our studies with relatively young (median age 44 years, N=293) 
Hispanic women with breast cancer at varying points in survivorship, 35% had hypertension, 35% had 
heart disease; 15% had diabetes, and BMIs averaged 31.5, [range 19.7-54.1]. Prevalence of depression 
was 49% overall, and 59% among those who had received chemotherapy and radiation. While these 
women were not specifically assessed at the end of chemotherapy, depression is expected to be higher at 
the end of treatment.61 
 
 
5.0 
RESEARCH DESIGN, METHODS AND PROCEDURES  
 
Describe research design, methods and all study procedures   
 
Design. Using the SMART design (Figure 1), we will recruit 430 survivors finishing curative intent 
chemotherapy or chemo-radiation for a solid tumor at the NCI-designated University of Arizona 
Comprehensive Cancer Center (UACC, Tucson and Phoenix locations) and at Arizona (AZ) community 
oncology settings (post attrition N=344). Following consent, we will collect all further data and deliver 
interventions over the telephone from the central study office. The study Coordinator will conduct 
recruiter training. Training will include didactic information, role-playing, and return demonstration of 
recruiting per script. Study participants will be informed that they will be 1) randomization to SMSG or 
TIP-C+SMSG and may be re-randomized after 4 weeks to either continue with the SMSG alone or to 
add TIP-C, 2) telephone symptom assessment and intervention sessions are weekly, and 3) there is no 
cost to study participation. Further, 4) the study lasts 13 weeks to include all data collection, 5) 
Interventions are designed to help reduce symptoms, 6) A review of potential risks/benefits; and 7) there 
are study incentives. 
 
Following baseline interview, symptom management need (high versus low need) will be determined. 
The low need group will not receive interventions but will be followed up at week 4 for a brief symptom 
assessment and at week 13 for the exit interview. The survivors in the high need group will be randomly 
assigned to either: 1) SMSH alone or 2) TIP-C+SMSH for 8 weeks followed by continued 4 weeks of 
SMSH alone. We will mail the SMSH, printed in the survivor’s preferred language, to the survivor 
following randomization. All high need participants will receive weekly telephone contacts during 
weeks 1-12 to assess symptoms, deliver the assigned intervention, and assess intervention enactment and 
fidelity.  
 
After the initial 4 weeks in the SMSH alone group, the survivor’s response on depression will be 
determined (see Survivor’s symptom response). Responders will continue with the SMSH only for 
another 8 weeks. Survivors who do not respond on depression will re-randomized to either continue with 
the SMSH alone or add TIP-C to test the value added by the more intensive intervention. Those initially 
randomized to TIP-C+SMSH will not be re-randomized. Total duration of each of the three intervention 
sequences is 12 weeks: SMSH alone; SMSH alone for 4 weeks followed by SMSH+TIP-C for 8 weeks; 
TIP-C+SMSH for 8 weeks followed by SMSH alone for 4 weeks. The 8-week duration of TIP-C 
establishing the intervention dose is based on our past work. Week 4 timing for response determination 
is founded on past work:137-139 where it was a change-point in the trajectory of the mean symptom 
severity, with median time to response on depression ranging from 14 to 24 days depending on patient 
and disease characteristics. Survivors in the low need benchmark group will also be assessed at week 4 
to track the natural resolution of symptoms. The interview at week 13 will occur for both the survivors 
in the high need group after completing the 12-week intervention and for the low need benchmark group 
to achieve comparability for time. Our preliminary data indicate that at 12 weeks post chemotherapy, the 
prevalence of symptoms is low in the benchmark group, and the interventions have the potential to 
manage symptoms for high need survivors. Week 13 will conclude the data collection and follow-up. 

 
 
 
 
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We will extract cancer and treatment information from the oncology medical records after survivors 
complete the study. 
 
Procedures.  
Determination of need for symptom management. High versus low need status of survivors will 
be determined using data from the baseline telephone interview conducted within after consent. 
The criteria for being in the high need group are at least one comorbid condition as reported by 
patients using the Bayliss instrument175 plus a CES-D96 score of 16 or higher or two or more 
comorbid conditions (not including cancer) regardless of CES-D score. Survivors not meeting 
these criteria will be assigned to the low need benchmark group and sent a letter indicating that 
they will be contacted at 4 and 13 weeks for follow-up assessments. 
 
High need group: randomizations. All high need survivors will be mailed a copy of the printed 
SMSH. In the first randomization, 52 survivors will be randomized to TIP-C+SMSH, and 172 
survivors will be randomized to SMSH alone to ensure a sufficient number to investigate 
intervention sequencing (see power analysis). Randomization will be completed using a computer 
minimization algorithm
176,177 programmed by Dr. Sikorskii that balances arms by recruitment 
location (UACC versus community clinics), site of cancer, and type of cancer treatment received 
(chemotherapy, chemoradiation, chemotherapy followed by radiation therapy, hormonal therapy or 
trastuzumab).
176 The minimization is superior to stratified randomization and is well-suited for the 
design, as the groups are balanced dynamically with respect to selected variables, with each 
subsequent randomization targeting any imbalances between the groups that may have occurred 
previously. The second randomization will have a 1:1 ratio but the same balancing factors. It will 
occur after 4 weeks among non-responders to SMSG alone on depression, a sentinel symptom that is 
associated with other symptoms
68-71 and a barrier to their self-management,
37,114,115 based on our 
scientific premise. 
 
Survivor’s symptom response. Response to the management of each of 15 symptoms will be 
assessed using the symptom severity ratings from the General Symptom Distress Scale (GSDS) 
administered during weekly calls and interference-based cut-points for moderate or severe symptoms 
developed and validated in past work of this team.97 Our approach overcomes the drawbacks of other 
approaches that are based on absolute or percent change178,179 in severity, and anchors symptom 
responses to significant reductions in symptom interference with enjoyment of life, relationships with 
others, general daily activities, and emotions. As the symptom severity rating increases from 0 (not 
present) to 10 (worst possible), symptom interference increases as well, but does so in a non-linear 
way. The increase of one unit on the severity rating scale may have a different meaning in terms of 
symptom interference depending on where on the scale the increase occurs. The cut-points for mild, 
moderate, or severe symptom categories mark the places on a 0-10 scale where the largest increases 
in interference occur. The cut-points vary for different symptoms, reflecting their different degree of 
interference with daily life. For depression, the none/mild category corresponds to severity scores of 
0-1, moderate category corresponds to scores 2-3, and scores of 4-10 are the severe category. For 
pain and fatigue, the none/mild category corresponds to severity scores of 0-1, the moderate category 
corresponds to scores 2-4, and scores of 5-10 fall into the severe category. For insomnia and 
numbness, the none/mild category is 0-3, moderate is 4-6, and severe is 7-10. We define onset for 
each symptom as the date when a symptom first reached moderate or severe according to these cut-
points. Survivors who started at severe at onset and ended at moderate or mild at a given time point 
(e.g., week 4), and survivors who started at moderate and ended at mild, will be called responders for 
the specific symptom.97 Thus a survivor may be, for example, a responder on pain and depression, 
and non-responder on fatigue. Symptom cases that remain or become moderate or become severe at 

 
 
 
 
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week 4 are classified as non-responders. We have selected response on the symptom of depression as 
a criterion for re-randomization at week 4 based on our scientific premise. 
 
Interventions. This project will test two interventions: a Symptom Management and Survivorship 
Handbook (SMSH), and a Telephone Interpersonal Counseling (TIP-C). The SMSH is an evidence-
based self-care management guide. The printed SMSG has specific symptom modules written at the 8th 
grade level.84 Management strategies for each symptom are based on the National Comprehensive 
Cancer Network (NCCN) guidelines and the Oncology Nursing Society Putting Evidence into Practice 
(PEP) guides.83,88 Modules on survivorship are based on the American Society of Clinical Oncology 
(ASCO) Guidelines for breast and colorectal cancer survivors.105,106 A research assistant assesses 
symptoms and refers survivors to the specific SMSG sections for elevated symptoms during weekly 
phone calls. In past studies, survivors were satisfied with this intervention and reported decreased 
symptom burden and improved psychosocial status.107  
 
The Telephone Interpersonal Counseling (TIP-C) Intervention, based on interpersonal 
psychotherapy, has been shown to decrease psychological symptoms in past studies.108-111 Social workers 
(called counselors) with a master’s degree and psychiatric-mental health and oncology expertise deliver 
the TIP-C intervention via weekly calls. Counselors use interpersonal communications techniques to 
focus on depression, anxiety, and the interpersonal interactions between the cancer survivor and others. 
The counseling addresses 1) mood and affect management, 2) emotional expression, 3) interpersonal 
communication and relationships, 4) social support, and 5) follow-up, resources and referral to resources 
(e.g., financial). Negative psychological symptoms were shown to decrease with TIP-C in past studies 
108-112 Other symptoms decreased with TIP-C,113 which is consistent with the literature documenting the 
co-occurrence of depression with other cancer- and treatment-related symptoms 68-71 and that when 
depression is treated, other symptoms improve. 
 
We will deliver interventions by telephone at convenient times for the survivor, including evenings and 
weekends, in English or Spanish, based on the survivor’s preference. Section 7.0 details the intervention 
procedures for this study. 
 
Methods 
Dynamic intervention sequencing. By individualizing intervention sequences, this research 
overcomes a static approach to intervention delivery116-118 by stepping up intervention intensity based on 
the survivor’s demonstrated needs. We have established the efficacy of both TIP-C and SMSH (see 
section titled preliminary studies) in traditional RCTs. In the proposed study, we will investigate their 
optimal sequencing to address heterogeneity of response using a SMART design.119-122 Our approach 
begins with one intervention, and then at a decision point typical in clinical practice, we will evaluate 
therapeutic response (as detailed in section on Survivor’s Symptom Response). The analysis of data 
from this SMART will provide an evidence base for a decision to either give one intervention more time 
for symptom resolution or intensify by adding a second therapeutic modality. Currently, such decisions 
have a limited evidence base using individuals’ characteristics. We will address this gap in science by 
building algorithms for allocating intervention resources in a way that leads to the best possible survivor 
outcomes using the most labor-efficient intervention to achieve those outcomes. 
 
 
 

 
 
 
 
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Conceptual framework. This study is 
informed by the NIH Symptom Science 
Model.123 In our adaptation (Figure 2), 
depressive and other symptoms (e.g., 
fatigue, insomnia, pain) experienced by the 
survivor following chemotherapy are 
managed using the SMSG and TIP-C 
interventions124 through key mediating 
variables, self-efficacy and social support, 
as tested in Hypothesis 3. By the design of 
these interventions, symptom improvement 
occurs in part by increasing self-efficacy to 
perform tasks (e.g. symptom management) 
125-128 and mobilizing social support.129 The 
mediated relationship of the 
intervention on symptoms may be 
influenced by “context of care” variables130 
that include socio-demographic, disease 
and treatment characteristics, the extent of 
intervention receipt and enactment,131 and 
language of delivery that reflects the participant’s preference and culture. These variables are considered 
as potential moderators in the exploratory aim of this study. Due to randomizations, these variables will 
be equally distributed among groups and will not affect the estimates of main intervention effects in 
Hypotheses 1-3. However, given these variables, intervention effects may differ for individuals, and 
these variables provide a pool of potential tailoring factors for the decision rules for choosing optimal 
intervention sequences (exploratory aim). For example, the analysis may determine that younger 
survivors do best with a simple SMSH for 12 weeks, while older survivors need TIP-C+SMSH at the 
end of chemotherapy to achieve optimal outcomes. Other context of care variables may warrant SMSH 
alone for 4 weeks with possible later step-up based on 4 weeks of data. 
 
Preliminary Studies.  
Evidence of the efficacy of the TIP-C intervention. Drs. Badger and Segrin, developers of the TIP-C, 
have tested it against attention control (AC), telephone health education (THE) or exercise.43,140,141 
Survivors were recruited together with their friend or family caregivers and randomly assigned to either 
TIP-C or a comparison group in each study and completed at least three assessments over time. TIP-C 
focuses on the psychological distress of the survivors and their interpersonal interactions with others. 
During 30-minute weekly sessions, counselors address 1) mood and affect management, 2) emotional 
expression, 3) interpersonal communication and relationships, 4) social support, and 5) follow-up and 
referral to resources (e.g., insurance, financial). Findings from our initial study141 showed survivors’ 
depressive symptoms decreased over time for dyads in all groups (TIP-C, AC, exercise), and anxiety 
decreased in the TIPC and exercise groups. Based on initial testing and results of a meta-analysis, the 
TIP-C protocol was extended from 6 to 8 weekly sessions because those who were most depressed did 
better with more sessions/time.142 In the next two studies42,43,113 and in our ongoing study with Latina 
dyads (current N=238 dyads, final N=250 dyads) which will be completed by December 2017,143 we 
found significant decreases over time in depression, anxiety, negative affect, symptom distress and 
higher social support for survivors and caregivers, with TIP-C superior to THE on outcomes listed in 
Table 2. These preliminary data provide evidence for the efficacy of the TIP-C for managing depressive 
symptoms. 
 

 
 
 
 
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Evidence for the efficacy of the SMSH. Drs. B. and C. Given, developers of the SMSH, have tested it in 
4 RCTs with Dr. Sikorskii. Automated telephone symptom management using the SMSH was not 
different from nurse-assisted symptom management (N=437),138 previously found efficacious against 
control.144 Both arms achieved clinically significant reductions in symptom severity over baseline. In a 
recent study with 272 survivors treated with oral oncolytic agents,145 significant declines in symptom 
severity in the SMSH+ oral agent reminders arm compared to attention control were found post 
intervention (p=.02). These studies provide evidence of the efficacy of SMSG for managing multiple 
treatment-related symptoms. 
 
Telephone delivery of the interventions and data collection. In our initial studies, we used the telephone 
to deliver the interventions to remove access barriers to intervention receipt. Barriers are geographic 
access (e.g., rural), transportation costs, stigma, and the technology-associated anxiety and costs 
associated with internet delivery methods. Nationally, most people (98%) have telephone access146 
whereas internet and computer access is less universal. Adherence to a telephone intervention in our past 
studies was approximately 85% which is double that for face-to-face counseling.147 In our past work, 
we found intervention delivery via face-to-face, videophones, internet, and interactive voice response 
systems inferior to a live person on the telephone with respect to adherence and participant satisfaction. 
Consistent with findings of others148, we found that telephone collection reduces missing data (<5%). 
For our participants with lower education and literacy, data collection is better when they can ask 
questions immediately. Finally, by using uniform telephone assessments in all arms, the effects of the 
mode of administration of symptom assessments will be avoided.149 After careful consideration, we 
will use the telephone for intervention delivery and data collection to facilitate success and scientific 
rigor of this project. 
 
Delivery of the intervention in either English or Spanish. We have successfully delivered the TIP-C 
intervention in Spanish from bilingual bicultural counselors in a way that is culturally competent. We 
have incorporated Latina/o cultural values (see C5e) and beliefs about the importance of immediate and 
extended family and close friends in health outcomes.15 
 
Training and intervention fidelity. Intervention fidelity will be assessed through established methods 
outlined by the NIH Treatment Fidelity Workgroup on consistency in dose, providers, delivery, and 
receipt of the intervention.183 TIP-C interventionists (called counselors) will receive 24 hours of 
education, augmented by additional books and articles, about cancer diagnosis and treatment, 
psychological distress, and interpersonal counseling techniques with training protocols developed in 
previous studies.150,154,184,185 The interventionist will listen to 8-10 hours of counseling sessions recorded 
for training purposes. Drs. Badger and Segrin will conduct intervener training that will continue until the 
interveners are rated as achieving > 90% on protocol implementation. Annual re-training will occur 
throughout the study. The intervention fidelity protocols used in past studies will be applied in this 
study. All sessions are digitally recorded and about 10% randomly reviewed throughout the study to 
maintain quality, with written and verbal feedback to the counselors. Drs. Badger and Segrin will 
supervise the intervention quality control activities. Through weekly supervision, we will maintain 

 
 
 
 
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intervention fidelity and counselor adherence to protocols. We will evaluate adherence (number required 
elements discussed/ total number of elements).113,151,186 Drs. Badger and Segrin will listen to all sessions 
in English from the first 5 survivors (10 hours of supervision) and then randomly review 10% of 
sessions throughout the study. A bilingual counselor will review Spanish sessions using established 
protocols as in past studies. Counselors who do not maintain 90% adherence will not receive new cases 
until retraining has occurred, and Drs. Badger or Segrin will assume responsibility for those existing 
cases. Following retraining, 5 survivors will be monitored to insure that >90% adherence is achieved 
and then we will return to randomly selected monitoring for quality control. After a second retraining, 
we will replace counselors if unable to adhere to the protocols. Counselors deliver only the intervention 
for which they have training: 1) one for TIP-C +SMSH and 2) a different interventionist for SMSG 
alone. SMSG alone training will take less than two hours based on previous work by Dr. Sikorskii. 
 
Intervention reproducibility. Interventions are standardized, yet the complexities of depressive 
symptoms demand a flexible approach to preserve the relevance of TIP-C for the survivor. We will 
determine the number of elements personalized to the specific needs within the structured protocol 
(number of personalized elements/ total number of elements). We will then examine the effect of 
personalization (e.g., more discussion of socioeconomic needs with one participant vs. another), if any, 
on outcomes. Counselors will keep detailed field notes after each session assessing intervention length, 
rapport, responsiveness, topics discussed, homework completed and satisfaction. Our past adherence 
rate of >85% far exceeds the rate reported for community mental health patients who return for face-to-
face appointments.187 Participants who miss (occurrence is rare) reschedule the session and as we will 
obtain multiple points of contact (e.g., home, cell, work telephone, e-mail address). If we fail to contact 
within the week, we will schedule the following week. We will document attrition rates and reasons. 
 
6.0  MEASURES/DATA COLLECTION INSTRUMENTS   
Describe all forms, questionnaires, instruments or other specific methods used to collect data. 
Include complete copies of all forms, interview guides, survey questionnaires, in Appendix I.  
 
Data Collection 
 
Interviews. All survivors will have data collected twice via telephone interviews: baseline and study 
week 13. The interviews will take 30-45 minutes. If a participant becomes fatigued, we will divide the 
telephone interview into two phone calls within the same week. Few participants requested such 
accommodations in past studies. Respondent burden is minimum and distributed over the course of the 
study. The interviewers at baseline and week 13 will be blinded to survivor’s need status or intervention 
sequences received. The study Coordinator will train interviewers via didactic information, written steps, 
and role-playing for difficult interview questions. In addition, 10% of all interviews are recorded for 
quality assurance (QA). 
 
Weekly Calls. Weekly symptom assessments are part of the delivery of SMSH and TIP-C interventions 
for the high need group (see section 7). At week 4, the study Coordinator will make a symptom 
assessment call to the survivors in the low need group using the GDSD to assess their natural symptom 
resolution. 
 
Medical Records. Recruiters will extract medical records information after survivors complete the study. 
 
Measures 
All measures have good reliability (α >.80)38,150,185,188 and validity, have been translated, and tested with 
Spanish speaking participants in our pilot studies.39, 180 Patient Reported Outcomes Measurement 
Information System (PROMIS)189,190 measures have been developed using sophisticated measurement 

 
 
 
 
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techniques, tested with over 21,000 individuals, calibrated to produce t-scores based on the general 
population, and are available in either English or Spanish. Measures are in Appendix A. 
 
Primary outcome 
Symptoms will be measured using the adapted General Symptom Distress Scale (GSDS),190,191 that 
allows for a quick assessment of symptoms, which is especially important during weekly calls. It 
evaluates 18 symptoms: fatigue, sleep difficulties, pain, headache, difficulty concentrating, lack of 
appetite, nausea, vomiting, constipation, diarrhea, numbness or tingling, skin rashes, swelling, weakness, 
shortness of breath, cough, depression, anxiety. Respondents indicate presence of each symptom (yes/no) 
and rate their severity if present on the scale from 1 to 10. The ability to manage symptoms is also 
assessed on a scale from 0=cannot manage to 10=can manage extremely well. The GSDS has good test-
retest and internal consistency reliability (≥0.8) and predictive and construct validity in both English and 
Spanish.191 A summed symptom severity index will be derived from each weekly contact, baseline, and 
13-week interviews. 
 
Secondary outcomes 
We will consider responses that are specific to each of the multiple symptoms that will be treated as 
nested within survivors. Response on depression will be applied as the criterion for re-randomization at 
week 4. Responses for all 15 symptoms during weeks 1-13 will be defined for Hypothesis 1, and 
responses during weeks 5-13 will be defined for Hypothesis 2. For responders, time to response will be 
defined as time in days from symptom onset to the date of the first sustained improvement among 
none/mild, moderate or severe categories. For non-responders, time to response will be treated as 
censored according to the principles of survival analysis. 
Depression. The Center for Epidemiologic Studies – Depression (CES-D) scale is a widely used measure 
of depressive symptoms within non-psychiatric populations.92,192,193 This measure has a reliability 
exceeding .90. At baseline, it will be used for need status determination, and at week 13 it will provide an 
additional measure of depressive symptoms to supplement the GSGS depression item. 
Comorbidity. Comorbidity will be measured with the Bayliss tool that queries the presence of 20 
comorbidities175 and used for need status determination at baseline. The internal consistency reliability is 
not applicable to a checklist. 
Potential Mediators. PROMIS short forms (SF) have established validity and α >.80. 189,190,194 
Self-efficacy. The PROMIS 8-item SF will be administered in interviews.195-198 Self-efficacy symptom 
management will also be captured by the GSDS item described above during interviews and weekly 
calls.  
Social support. The PROMIS 8-item SF for instrumental and emotional support will be used in 
interviews.195-198 
 
7.0 
DETAILED DESCRIPTION OF INTERVENTION 
Describe in detail for intervention studies or indicate otherwise by checking below:  
 
Two interventions with proven efficacy 4,37-39 will be used: 1) a minimal intervention, the printed 
Symptom Management and Survivorship Guide (SMSG) with evidence-based self-care strategies for elevated 
symptoms and 2) a more intensive intervention that combines SMSG with a Telephone Interpersonal Counseling 
(TIP-C) intervention for managing depressive symptoms.39,40 
 
a). Symptom Management and Survivorship Handbook (SMSH) contains 15 symptom-
specific modules for the symptoms assessed in this study. Each module has an identical format 
(Frequently Asked Questions): what the symptom is, how people describe the symptom, the causes of 
the symptom including medications, and a set of strategies presented in bullet points for managing the 
symptom. For each symptom, there are indications as to when and for what reasons to contact the health 

 
 
 
 
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care provider and other resources are listed for management. Modules on survivorship are based on the 
American Society of Clinical Oncology (ASCO) Guidelines for breast and colorectal cancer 
survivors.105,106 The previously tested English version was translated into Spanish using an adaptation of 
Brislin’s translation/back translation process180 used by this team in the past. Professor Jaime Fatás-
Cabeza, Director of the Undergraduate Translation and Interpretation Program in the Department of 
Spanish and Portuguese at the University of Arizona, oversaw the translation of the SMSH, producing a 
Spanish language version suitable for readers with an 8th grade education. Three cultural experts 
performed back translations of a random sample of pages from the SMSH for comparison to the original 
English language versions, and all discrepancies between the back translated and original English 
language pages were corrected. The translated version was discussed in a focus group of six Spanish-
speaking Latinos in terms of understandability (language level and complexity), use of idioms, and 
consistency of meaning. 
 
All high need survivors will be mailed the SMSH in English or Spanish (participant preference), 
following the completion of the baseline interviews. During each week, the research assistant (RA) 
trained by the study Coordinator will call the survivors. The first week call will begin with the 
assessment of symptoms using the GSDS (described in the Measures section). For each symptom rated 
at 4 or higher on a 0-10 scale of severity, the survivors will be referred to the SMSH for symptom self-
management. The threshold of 4 was selected based on the NCCN guidelines for symptom monitoring 
and management83 and used successfully in past work. 75,76,81,82,89 When a symptom is rated at a 7 or 
higher on the 0-10 scale, patients will be asked to contact their health care provider. During weeks 2-12, 
calls will begin with assessment of SMSH use since the last call (intervention enactment), followed by 
the administration of the GSDS and referral to the SMSH for any above threshold symptoms. Calls will 
last approximately 10 minutes. 
 
b). Telephone Interpersonal Counseling Intervention (TIP-C). The 8-week TIP-C 
intervention is detailed in Table 3 and social workers with a master’s degree and psychiatric-mental 
health and oncology expertise deliver TIP-C weekly. During weekly contacts, the counseling targets 
social support behaviors using interpersonal communications techniques. Interpersonal communication 
facilitates processing stressful affective reactions to a cancer diagnosis and treatment, marshalling 
instrumental support for assistance with roles and functions, informational support for advice and 
information, and appraisal support for gauging and adjusting to the stressor. Interventionists can 
personalize the counseling intervention for the specific needs or interests as expressed during sessions 
while still adhering to a structured protocol. For example, one survivor may need to focus on depression 
and family issues (e.g., role transitions such as job loss) rather than on anxiety and resource issues (e.g., 
transportation, lack of insurance). This approach is consistent with cancer survivorship care 
recommendations 181 and recent evidence showing that improved psychological well-being occurs when 
an intervention addresses practical resource needs (e.g., finances).182 

 
 
 
 
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8.0 
STATISTICAL CONSIDERATIONS 
Analysis Plan for answering objectives including endpoint definitions, patient accrual 
objectives, and estimated duration of study. This section should be developed in consultation 
with appropriate biostatistician. 
 
 
 
Potential Covariates and Future Tailoring Variables. Demographic characteristics include survivors’ 
age, education, work, ethnicity, race, acculturation, and marital status, and language of intervention 
delivery. Receipt and enactment of intervention strategies are measured during weeks 1-12. Receipt is the 
number of completed weekly sessions. Enactment of the SMSH strategies is assessed at the beginning of 
calls during weeks 2-12. Enactment of the TIP-C will be measured by tracking the implementation of 
behaviors discussed and completion of the assigned homework as documented in counselor’s field notes 
for each session. Survivors’ chart data will include radiation, surgery, chemotherapy, targeted or 
hormonal therapy (dose, type, dates received), co-morbidities, cancer site and stage, and medications 
(e.g., supportive agents for symptoms) corresponding with the time-on study. 
 
Scientific Rigor and Transparency. The scientific rigor of this study is ensured by the randomized 
design and complete inclusion/exclusion criteria defining the population to which findings would be 
generalizable. We also have a reproducible manualized protocol for the interventions, tracking of 
intervention fidelity, dose, receipt and enactment, use of measures with solid evidence of reliability and 
validity, blinding of data collectors and transparent assessment and statistical analysis plans including 
attention to biases and the missing data. 
 
Sex as a biological variable. We expect more than 50% of the sample to be female (Human Subjects 
section). We will consider sex as covariate and a potential future tailoring variable in the exploratory aim. 
 
Analytic Methods 
Data management. Data will be entered into the secure web-based database that will be accessible to 
recruiters, interveners and interviewers. The RA will perform quarterly quality assurance checks of the 
data, supervised by Dr. Sikorskii. De-identified data will be transferred into SAS 9.4 for analyses. 
Distributions of outcomes and potential covariates will be summarized. Outliers will be investigated by 
inspecting the residuals, and models described below will be fit with and without outliers to examine 

 
 
 
 
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their influence on the results. Sensitivity to the degree of personalization of TIP-C (see C7d) will be 
examined by relating it to the primary outcome at week 13 for those who received this intervention. 
 
Attrition Analyses and Handling of Missing Data. Attrition will also be compared between each pair of 
randomized groups. In addition, we will compare characteristics of those who completed the study with 
those who did not within their designated group to inform the generalizability of findings. The regression 
techniques described below allow for missing at random (MAR) mechanism.199 If patterns of missing 
data indicate potential not missing at random (NMAR) mechanisms, then models describing missing 
mechanisms will be considered (e.g., pattern-mixture models),200,201 and sensitivity analyses will gauge 
the robustness of the results. 
 
Primary Analysis. The intent-to-treat principle will be followed. 
Aim 1. Hypothesis 1 will be tested using statistical model #1 that relates repeated measures of the 
survivor primary outcome y (summed severity index) to the group assignment variable 𝑥𝑥1, outcome at 
baseline 𝑥𝑥2, time entered as a class variable to model potentially non-linear patterns, and other covariates. 
Because the symptom severity index is expected to follow a right-skewed distribution, this model will be 
fit as a generalized linear mixed effects (GLME) model with gamma distributed errors. The main effects 
of the group variable 𝑥𝑥1 (average difference over time between groups created by the first randomization) 
will be tested. While summed symptom severity is a succinct outcome summarizing 15 symptoms, it has 
its drawbacks that will be overcome with the next analysis that focuses on specific symptom responses 
(secondary outcomes). The unit of analysis will be symptom case. Cases reaching moderate or severe at 
baseline or any time during weekly calls will be analyzed. Symptom responses and times-to-response 
defined under measures will be analyzed using methodology described by Sikorskii et al.97 Patient 
symptom responses are treated as multiple events, and associations among responses to multiple 
symptoms nested within patients will be accounted for in the GLME model with binomial errors. 
Marginal Cox proportional hazard models with a robust sandwich covariance matrix estimate 
implemented in PHREG procedure in SAS203,204 will be employed for the analysis of multiple times to 
response nested within survivor. Symptom- and survivor-level covariates will be included in the model, 
and different intervention effects for different symptoms will be evaluated. For randomized arms, dummy 
variables 𝑥𝑥1,1, … 𝑥𝑥1,15with two levels (corresponding to randomized group assignment) will be created 
to model possibly different effects of interventions across 15 symptoms. With the marginal Cox model, 
times to 15 types of events (specific symptom responses) will be considered. First, the equality of beta 
coefficients for the study group across symptoms will be tested. If, based on this test, the effects of the 
study group are different across symptoms, then tests for the equality of each coefficient to zero will 
yield the tests of the intervention effect on each of the 15 symptoms. If the effects are not significantly 
different across symptoms, then the model will be modified to include only one two-level group variable; 
the test of equality of its coefficient to zero will yield the formal test of Hypothesis 1. 
Hypothesis 2. The strategy described under the analyses for Hypothesis 1 will be implemented for the 
repeated outcome measures during weeks 5-13 that will be related to group assignment from the second 
randomization, summed symptom severity during week 4, time, and covariates. Analyses for symptom 
responses and times to response will also be similar to those described above except we will use weeks 5-
13 instead of weeks 1-13, and groups created by the second randomization. 
Hypothesis 3. To test for mediation, study group will be treated as the independent variable and each of 
the potential mediators (one at a time) will be tested for their effect on the primary outcome variable at 
week 13, controlling for its baseline value. We will use a bias corrected bootstrapping analytic strategy205, 
206 based on 5000 bootstrap samples to estimate confidence intervals around the indirect effect of study 
group on the primary outcome, through the mediator. To establish mediation, the 95% confidence 
interval around the indirect effect must not include 0. 

 
 
 
 
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Aim 2. Benchmarking of the outcomes produced by three intervention sequences against the low need 
group will be accomplished using a 4-level variable (0=low need referent level, 1=SMSH alone for 12 
weeks, 2=TIPC+ SMSH for 8 weeks then SMSG alone for 4 weeks, 3=SMSH alone for 4 weeks then 
TIP-C+SMSH). We will be repeating the analyses described under Hypotheses 1 and 2 with this new 
variable and data from weeks 4 and 13. Because the low need group was created by screening and not by 
randomizations, there will be no causal conclusions drawn from the comparisons of levels 1-3 to the 
referent level. However, these comparisons will help gauge the clinical significance of the improvements 
due to the interventions in the high need group. 
 
Exploratory Aim. The characteristics of responders will be compared to those of non-responders using t-
tests, chi-square or Fisher’s exact tests. Characteristics found to differ, along with mediators and other 
covariates listed in section C9d will be further considered as potential future tailoring variables. The 
optimal intervention sequences will be formed by identifying tailoring variables and determining the 
optimal decision rule (𝑑𝑑1, 𝑑𝑑2) specifying the first and second intervention to achieve optimal outcome 
given the values of the tailing variables. The analysis approach to this aim follows the Q-learning 
optimization method175,207-209 implemented in SAS PROC QLEARN.210,211 The Q-learning algorithm 
proceeds from right to left in Figure 1, i.e., backwards from the last decision to the first. Two Q-functions 
will be considered. The function 𝑄𝑄2(𝐻𝐻2) = 𝐸𝐸[𝑌𝑌2|𝐻𝐻2] is the expectation of the second stage outcome 𝑌𝑌2 
given history after 2 stages (weeks 1-13, denoted by 𝐻𝐻2): survivor characteristics, outcomes observed 
during weeks 1-13 and interventions received. The function 𝑄𝑄1(𝐻𝐻1) = 𝐸𝐸[𝑌𝑌1 + max 𝑄𝑄2(𝐻𝐻2)] uses history 
through the first intervention stage 𝐻𝐻1, weeks 1-4.The conditional expectations in the Q-functions will be 
estimated from the mixed model analyses for the summed severity index, and the optimal decision rules 
will be found using backward induction by optimizing these functions.212,213 The resulting tailored 
decision rules can then undergo formal testing in a future confirmatory RCT. 
 
Potential Difficulties/Limitations and Alternative Approaches 
Table 4 shows the project timeline. Potential problems from recruitment and retention will be minimized 
by the use our previous methods yielding high retention rates with no differential attrition between 
conditions. Potential problems in intervention delivery are minimized by implementing protocols for 
intervention fidelity. There are no high-risk aspects of this trial, and all procedures are non-invasive. We 
recognize that in addressing depression our efforts might inadvertently produce detrimental psychological 
responses. Should this occur, our experienced interventionists will refer the survivor to mental health 
services. Because randomizations may not account for all possible error sources, we will adjust for 
baseline values of outcomes in the analysis to provide added control over pre-intervention influences. All 
outcomes and hypotheses are stated a priori. In the exploratory analyses, multiple testing will be 
addressed by employing the Benjamini- Hochberg or Hochberg adjustment214-216 to control the false 
discovery rate. 
 

 
 
 
 
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9.0 
STUDY TIMELINE 
 
List of all parameters and required intervals for observations, measurement of outcomes, 
intervention and intervals at which it is given.   
 
Table 5 represents the protocol using the SMART design schema in Figure 1. Forms required of 
protocol include: Baseline and week 13 follow-up questionnaires (T2), debriefing and satisfaction 
questionnaire (T2), GSDS, SMSH form (internal only), TIP-C form (internal only). 
 
    Table 5: Protocol  
Time 
Actions 
Enrollment 
Recruit, Enroll, Consent, Set up Baseline Assessment 
Baseline 
(week 0) 
Baseline Assessment with all questionnaires by Data Collector-may or may not be 
interventionist assigned. 
Data Collector completes notifies Project Coordinator that interview has been completed. 
Screening  
and 
stratification 
into low 
versus high 
need (week 0) 
Project Coordinator will look up need status in the database. Logic programmed in 
RedCap based on no co-morbidity (Bayliss tool) and CES-D score in baseline interview:  
Low need benchmark stratum: no or some comorbid conditions and NO depression 
(CESD <16).  
High need stratum: 1 or more comorbid condition and CESD of 16 or higher OR 2 or 
more comorbid conditions (not including cancer) regardless of CES-D score.  
 
Low need 
benchmark 
stratum 
High need stratum 
 
 
Project Coordinator will run randomization program to allocate 
high need survivors to either SMSH or SMSH+TIP-C. 
Interventionist assigned and will set up first session, mark calendar 
for the other sessions over 12 weeks 
 
SMSH in the first randomization 
SMSH+TIP-C in the 
first randomization  
Week 1 
Nothing  
Session 1- On the Handbook form, 
document GSDS symptoms and chapters 
referred.  
Set up/confirm next appointment. 
Session 1- On the 
Handbook form, 
document GSDS 
symptoms and 
chapters referred.  
Conduct TIP-C per 
protocol. Complete 
the TIP-C form.* 
Set up/confirm next 
appointment 
Week 2 
Nothing  
Session 2- On the Handbook Form, 
document what was done, GSDS 
symptoms, and handbook chapters 
referred. Set up/confirm next appointment. 
Session 2 - On the 
Handbook Form, 
document what was 
done, GSDS 
symptoms, and 
handbook chapters 
referred. 

 
 
 
 
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Conduct TIP-C per 
protocol. Complete 
TIP-C form.*  Set 
up/confirm next 
appointment. 
Week 3 
Nothing 
Session 3- On the Handbook Form, 
document what was done, GSDS 
symptoms, and handbook chapters 
referred. Set up/confirm next appointment. 
Session 3- On the 
Handbook Form, 
document what was 
done, GSDS 
symptoms, and 
handbook chapters 
referred. 
Conduct TIP-C per 
protocol. Complete 
TIP-C form.*  Set 
up/confirm next 
appointment. 
Week 4 
On the week 4 low 
need group form, 
document 
symptoms using 
GSDS (data 
collector, not 
intervener). 
Session 4- On the Handbook Form, 
document what was done, GSDS 
symptoms, and handbook chapters 
referred. Set up/confirm next appointment. 
 
Remind survivor they may be continuing 
in this intervention or switched to 
SMSH+TIP-C for 8 more weeks (see 
protocol). 
Will have to call back and set up/confirm 
next appointment. 
Session 4- On the 
Handbook Form, 
document what was 
done, GSDS 
symptoms, and 
handbook chapters 
referred. 
Conduct TIP-C per 
protocol. Complete 
TIP-C form*.  Set 
up/confirm next 
appointment. 
After Week 4-
2nd 
randomization 
will occur 
No change 
Project Coordinator to determine 
survivor’s response on depression. In the 
baseline interview, use GSDS rating of 
depression to determine if depression was 
mild (0-1), moderate (2-3) or severe (4+).  
Then determine if depression was 
mild/moderate/severe at the last completed 
of weeks 1-4.  
If depression was mild at baseline and last 
week, then response. 
If depression was moderate/severe at 
baseline then became one category lower 
at last week, then response. 
Otherwise non-response (depression did 
not improve by one or more categories or 
did not stay mild). 
If response, continue with SMSH only.  
If non-response, Project Coordinator will 
re-randomize to either continue with 
SMSH only, or add TIP-C beginning with 
 

 
 
 
 
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week 5. 
 
 
SMSH only 
continued (response 
or randomized in the 
second 
randomization) 
SMSH+TIP-C in 
the second 
randomization 
SMSH+TIP-C in the 
first randomization 
Week 5 
Nothing 
Session 5 -  On the 
Handbook Form, 
document what was 
done, GSDS 
symptoms, and 
handbook chapters 
referred. Set 
up/confirm next 
appointment. 
 
Session 5- On the 
Handbook Form, 
document what 
was done, GSDS 
symptoms, and 
handbook 
chapters referred. 
Start TIP-C per 
protocol (session 
1 of TIP-C.  
Complete the 
TIP-C form.* 
Set up/confirm 
next appointment. 
Session 5- On the 
Handbook Form, 
document what was 
done, GSDS 
symptoms, and 
handbook chapters 
referred. Conduct 
TIP-C per protocol. 
Complete TIP-C 
form*.  Set 
up/confirm next 
appointment. 
Week 6 
Nothing 
Session 6 - On the 
Handbook Form, 
document what was 
done, GSDS 
symptoms, and 
handbook chapters 
referred. Set 
up/confirm next 
appointment. 
 
Session 6- On the 
Handbook Form, 
document what 
was done, GSDS 
symptoms, and 
handbook 
chapters referred. 
Conduct TIP-C 
per protocol 
(session 2 of TIP-
C). Complete 
TIP-C form. * Set 
up/confirm next 
appointment. 
Session 6- On the 
Handbook Form, 
document what was 
done, GSDS 
symptoms, and 
handbook chapters 
referred. 
Conduct TIP-C per 
protocol. Complete 
TIP-C form.*  Set 
up/confirm next 
appointment. 
Week 7 
Nothing 
Session 7 On the 
Handbook Form, 
document what was 
done, GSDS 
symptoms, and 
handbook chapters 
referred. Set 
up/confirm next 
appointment. 
 
On the Handbook 
Form, document 
what was done, 
GSDS symptoms, 
and handbook 
chapters referred. 
Conduct TIP-C 
per protocol 
(session 3 of TIP-
C). Complete 
TIP-C form.*  Set 
up/confirm next 
appointment. 
Session 7- On the 
Handbook Form, 
document what was 
done, GSDS 
symptoms, and 
handbook chapters 
referred. 
Conduct TIP-C per 
protocol. . Complete 
TIP-C form.*  Set 
up/confirm next 
appointment. 
Complete the TIP-C 

 
 
 
 
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form.   
Week 8 
Nothing 
Session 8- On the 
Handbook Form, 
document what was 
done, GSDS 
symptoms, and 
handbook chapters 
referred. Set 
up/confirm next 
appointment. 
 
On the Handbook 
Form, document 
what was done, 
GSDS symptoms, 
and handbook 
chapters referred. 
Conduct TIP-C 
per protocol 
(session 4 of TIP-
C).  Complete 
TIP-C form*.  Set 
up/confirm next 
appointment. 
Session 8- On the 
Handbook Form, 
document what was 
done, GSDS 
symptoms, and 
handbook chapters 
referred. 
Conduct TIP-C per 
protocol. Closure of 
TIP-C.   Complete the 
TIP-C form. * 
Set up/confirm next 
appointment to 
continue with SMSH 
only for the next 4 
weeks.  
Week 9 
Nothing 
Session 9- On the 
Handbook Form, 
document what was 
done, GSDS 
symptoms, and 
handbook chapters 
referred. Set 
up/confirm next 
appointment. 
 
Session 9- On the 
Handbook Form, 
document what 
was done, GSDS 
symptoms, and 
handbook 
chapters referred. 
Conduct TIP-C 
per protocol 
(session 5 of TIP-
C). Complete the 
TIP-C form. * Set 
up/confirm next 
appointment. 
Session 9- Document 
what was done on 
Handbook form, 
Assess with GSDS, 
document symptoms, 
handbook chapters 
referred. 
Set up/confirm next 
appointment 
Week 10 
Nothing 
Session 10- On the 
Handbook Form, 
document what was 
done, GSDS 
symptoms, and 
handbook chapters 
referred. Set 
up/confirm next 
appointment. 
 
On the Handbook 
Form, document 
what was done, 
GSDS symptoms, 
and handbook 
chapters referred. 
Conduct TIP-C 
per protocol 
(session 6 of TIP-
C). Complete the 
TIP-C form.* Set 
up/confirm next 
appointment. 
Session 10- Document 
what was done on 
Handbook form, 
Assess with GSDS, 
document symptoms, 
handbook chapters 
referred. 
Set up/confirm next 
appointment  

 
 
 
 
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Week 11 
 
All 
interveners 
should notify 
Project 
Coordinator 
when session 
12 is 
scheduled so 
that 
interviewer is 
assigned to 
set up week 
13 interview. 
 
Session 11- On the 
Handbook Form, 
document what was 
done, GSDS 
symptoms, and 
handbook chapters 
referred.  
Set up/confirm next 
appointment. 
 
Session 11- On 
the Handbook 
Form, document 
what was done, 
GSDS symptoms, 
and handbook 
chapters referred. 
Conduct TIP-C 
per protocol 
(session 7 of TIP-
C). Complete the 
TIP-C form. *Set 
up/confirm next 
appointment. 
Session 11- Document 
what was done on 
Handbook form, 
Assess with GSDS, 
document symptoms, 
handbook chapters 
referred. 
Set up/confirm next 
appointment 
Week 12 
 
Set up 
appointment 
for final 
assessment 
Data collector to 
call and set up T2 
assessment for 
next week. 
Session 12- On the 
Handbook Form, 
document what was 
done, GSDS 
symptoms, and 
handbook chapters 
referred. 
 Do closure as is final 
session.   
 
Thank participant for 
participation. Remind 
participant that 
someone (give name 
if have) will call for 
follow-up interview in 
about a week.   
Session 12- On 
the Handbook 
Form, document 
what was done, 
GSDS symptoms, 
and handbook 
chapters referred. 
Conduct TIP-C 
per protocol 
(session 8 of TIP-
C). Complete 
TIP-C form.*   
Closure as is final 
session. 
 
Thank participant 
for participation. 
Remind 
participant that 
someone (give 
name if have) will 
call for follow-up 
interview in about 
a week.   
Session 12- Document 
what was done on 
Handbook form, 
Assess with GSDS, 
document symptoms, 
handbook chapters 
referred. 
Closure as is final 
session. 
 
Thank participant for 
participation. Remind 
participant that 
someone (give name 
if have) will call for 
follow-up interview in 
about a week.   
Week 13 
On the T2 Questionnaires, final Assessment with all Questionnaires-data collector 
Document additional debriefing questions (part of the T2 questionnaires). 
 
 
10.0 DATA SAFETY AND MONITORING PLAN 
 
Describe plans to monitor adherence to study protocol, integrity of data collection and 
intervention delivery.  Include any plans regarding project quality assurance. 
 
Data Safety and Monitoring Plan. This behavioral intervention study meets the definition of a clinical 
trial. Data and Safety Monitoring will be accomplished through multiple approaches: 

 
 
 
 
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Institutional Review Board (IRB) - All procedures related to data collection and safety will be approved 
by the University of Arizona (UA) Health Sciences Center IRB and by the independent Arizona Cancer 
Center Office of Clinical Trials. Processes will be established to guide collection, transfer and storage of 
data and training of staff to ensure data safety. Quality assurance (QA) reviews of data and staff will be 
performed as described below. 
 
1. Security Procedures for Collection, Transfer and Storage of Electronic Data. Electronic files will 
consist of enrollment data, survey data at two time points, symptom data collected during the weekly 
calls, interventionist call data for survivors allocated to TIP-C + SMSG and survivor’s medical record 
data (collected at enrollment and during medical record audit after survivors complete their 13 week 
interviews). First, enrollment data with identifiers will be stored separately from the study data. Second, 
all computers that will store data at the central location will be password protected. The system will 
have a secure login along with audit control mechanisms to meet the HIPAA guidelines. Third, servers 
will utilize state-of-the art security processes. Electronic copies of forms, such as the consent or HIPAA 
authorization form will be stored on a secure dedicated server with appropriate firewalls. The system 
will use encryption (SSL certificate) to transfer data between the machines. This technology is the same 
as that used for online e-commerce applications to protect consumer information. Servers are scanned 
for viruses and systems are in-place to detect attempts at unauthorized entry. All transactions to the 
database are stored in archive logs as re-do data and are accessible to enable quick recovery of all 
data should the need arise. Backup files are written nightly to back up servers. 
 
2. Security Procedures for Collection, Transfer and Storage of Paper Data. Paper files will consist of 
consent and authorization forms and medical record audits. Paper copies of all forms will be faxed to 
the central study office for data entry. Faxed copies of medical records will be retained in locked 
storage cabinets at UA accessible only to study personnel. 
 
3. Training of Staff. Recruiters will follow UA institutional processes for enrollment of patients to 
clinical 
trial(s). Training by the study Coordinator will occur in order to ensure recruiters understand eligibility 
criteria, study design and goals. Training will emphasize strategies to maximize enrollment and 
retention of minority participants. Additionally, training will occur to assure recruiters understand the 
function and importance of data gathered during the medical record audit at enrollment. Training will 
include completion of simulated cases. Booster training sessions will be scheduled as needed. 
Interviewers/Data Collectors - will be carefully instructed and trained in appropriate interviewing 
techniques and will receive regular monitoring by the study Coordinator to ensure the ethics of research 
and scientific integrity and protection of confidentiality. Participants are asked prior to each interview if 
they want to continue and are given a toll-free number to contact UA if they have questions or 
concerns. 
Interventionists- TIP-C interventionists will receive 24 hours of education, augmented by additional 
books and articles, about cancer diagnosis and treatment, psychological distress, and interpersonal 
counseling techniques with training protocols developed in previous studies (Appendix C). The 
interventionists will listen to 8-10 hours of counseling sessions recorded for training purposes. Drs. 
Badger and Segrin will conduct interventionist training that will continue until the interventionists are 
rated as achieving > 90% on protocol implementation. Annual re-training will occur throughout the 
study. 
Medical Record Auditors – will be the recruiters or are employees of each recruitment site with 
oncology experience but trained by the study Coordinator on collection of data for this study. 
Training will target job descriptions, and roles and responsibilities of group members and will consist of 
1) an overview of project objectives, theoretical framework, and research design and rationale, 2) 
background and training on collecting data free from bias, 3) information on scale and item response 

 
 
 
 
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Page 25 
 
issues; 4) protection of human patients and confidentiality issues; and 5) data and intervention 
monitoring and quality assurance procedures. Activities for training will consist of lectures, discussion, 
 
 
4. Monthly Meetings – Monthly meetings with all research staff will be conducted to review accrual, 
attrition, discuss problems and/or concerns and ensure everyone understands and is following the 
protocol. 
5. Quality Assurance Activities for Project Staff – Quarterly quality assurance (QA) will involve 
engaging in good data management activities. Procedures that include checking the integrity of data 
storage and examining frequency distributions to look for anomalies such as an excessive number of 
“don’t know” responses or problems with skip patterns will be in place. 
Recruiters – Enrollment data will be monitored monthly for completeness and consistency. If any 
missing data are identified, the completion of missing fields will be requested and questions clarified 
during quarterly QA review of the data. 
Interviewers - The level of quality of each interviewer and the interview process are monitored monthly 
by the study Coordinator and Investigators. A cadre of well-trained interviewers at UA is available and 
used by this team in previous studies. Early in the study, until proficiency is reached, the interviewers 
digitally record every interview for QA. Following initial training, interviewers will be required to 
record and submit 1 interview each month for review. There is no identifying information recorded. 
Booster training sessions are held with interviewers on a scheduled basis. Written feedback on the 
quality of the telephone interview is provided to all interviewers following review of each recording. 
Interventionists - All sessions are digitally recorded and about 10% randomly reviewed throughout the 
study to maintain quality, with written and verbal feedback given to the counselors. Drs. Badger and 
Segrin will supervise the intervention quality control activities. Through weekly case supervision, we 
will maintain fidelity of the intervention and counselor adherence to protocols. We will evaluate 
adherence (number required elements discussed/ total number of elements). Drs. Badger and Segrin will 
listen to all sessions in English from the first 5 dyads (40 hours of supervision) and then randomly 
review 10% of sessions throughout the study. A bilingual counselor will review sessions in Spanish 
using established protocols as in past studies. Counselors who do not maintain 90% adherence will not 
be given new cases until retraining has occurred, and Drs. Badger or Segrin will assume responsibility 
for those existing cases. Following retraining, 5 dyads will be monitored to ensure that >90% adherence 
is achieved and then we will return to randomly selected monitoring for quality control. Anyone unable 
to adhere to the standardized protocols is replaced after a second retraining. 
Data - Quality assurance reports will be prepared on a quarterly basis by the statistical research 
assistant supervised by Dr. Sikorskii and reviewed by the study Coordinator and investigative team. 
That is, for the internal audit, someone independent of the data collector will check the data. Data from 
10% of the recorded interviews and intervention sessions compared to database entries. The acceptable 
error rate is 0.3 %, i.e., 3 out of 1,000 fields. All errors are corrected during the QA check. Dr. Sikorskii 
will oversee preparation of the data report distributed to all investigators at least 5 days before the 
scheduled meeting. The report will include the summary of cumulative and quarterly accrual, 
randomization, cumulative attrition, and attrition by study group, gender, and race/ethnicity, adverse 
events and serious adverse events, data completeness and quality, and study Consolidated Standards 
of Reporting Trials (CONSORT) chart. Reports will also inform the Investigators about missing, invalid, 
or inconsistent data on selected key variables. For the external oversight, Dr. Jessica Rainbow who is 
not involved in the study has agreed to participate in QA meetings. 
 
6. Identification of Adverse Effects- The following will be considered serious adverse events (SAE): 
death, attempted suicide, major depression, breach of confidentiality. Death, attempted suicide and 
major depression would not occur as a direct result of study interventions, however, could be 
encountered during implementation of this study due to the inclusion criteria of cancer survivors. A 
breach in confidentiality may result from participation in this study. The investigators have successfully 

 
 
 
 
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Page 26 
 
trained staff to monitor and protect confidentiality of participants in large research studies conducted 
over the past two decades. Similar training strategies will be incorporated for training of staff in this 
study. Additionally, all research staff will complete the human subjects and HIPAA certification 
training. 
The following will be considered adverse events (AE): severe symptoms requiring hospitalization or 
urgent care. Again, severe symptoms are not expected to result from participation in this study but may 
result from cancer, its treatment or other existing comorbid conditions. 
 
Averse events and serious adverse events may be identified during implementation of the experimental 
protocols and are monitored by the Investigators in several ways. 
Interviewers: Interviewers may identify both serious adverse events and/or adverse events 
during completion of telephone interviews or telephone calls to schedule telephone interviews. 
Interventionists: The interventionists may identify both serious adverse events and/or adverse 
events during their telephone contacts with the participants. 
 
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14.0 APPENDICES 
 
APPENDIX I – FORMS 
 
• 
Recruitment Script 
• 
Contact Form (internal document) 
• Telephone survey (baseline and 13-week follow up) 
• Debriefing and satisfaction  
• Medical Record Audit Form (internal document) 
 
APPENDIX II – STUDY INFORMATION 
 
• 
Study Brochure 
• Study Flyer 
• Study webpage 
  
 
APPENDIX III – INTERVENTION INFORMATION 
 
• Symptom Management Toolkit 
• Weekly GSDS script 
• Handbook form (internal document) 
• TIP-C form (internal document)