Reducing Lung Cancer-Related Anxiety (RELAX)
Phase: NA
Conditions: Lung Cancer
Sponsor: Wake Forest University Health Sciences

 
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NCI Protocol #: WF 01213 
WF Protocol #: WF 01213 
IND # (If applicable): N/A 
 
Reducing Lung Cancer-Related Anxiety (RELAX) 
 
Research Base Name: 
 
 
Wake Forest NCORP Research Base  
Name of RB Principal  
 
 
 
Investigator: 
            Glenn Lesser, MD 
 
 
 
Wake Forest School of Medicine 
 
 
 
Department of Internal Medicine 
 
 
 
Section on Hematology and Oncology 
 
 
 
Medical Center Boulevard 
 
 
 
Winston-Salem, NC  27157 
 
 
 
Telephone: (336) 716-0891 
 
 
 
Fax: (336) 716-6275 
 
 
 
E-mail address: glesser@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: 
 
 
Wake Forest School of Medicine 
Co-Investigator: 
 
 
Kathryn Weaver, PhD 
 
 
 
Department of Social Sciences & Health Policy 
 
 
 
Division of Public Health Sciences 
 
 
 
Medical Center Boulevard 
 
 
 
Winston-Salem, NC 27157 
 
 
 
Telephone (336) 713-5062 
 
 
 
Fax (336) 716-7554 
 
 
 
E-mail address: keweaver@wakehealth.edu 
 
Organization:  
 
 
Wake Forest School of Medicine  
Co-Investigator: 
 
 
Gretchen A. Brenes, PhD 
 
 
 
Department of Psychiatry and Behavioral Medicine 
 
 
 
Medical Center Boulevard 
 
 
 
Winston-Salem, NC 27157 
 
 
 
Telephone (336) 716-1103 
 
 
 
Fax (336) 716-6830 
 
 
 
E-mail address: gbrenes@wakehealth.edu 
 
Organization:  
 
 
Wake Forest School of Medicine  
Co-Investigator: 
 
 
Timothy D. Howard, PhD 
 
 
 
Center for Genomics & Personalized Medicine Research 
 
 
 
Medical Center Boulevard 
 
 
 
Winston-Salem, NC 27157 
 
 
 
Telephone (336) 713-7509 
 
 
 
Fax (336) 713-7566 
 
 
 
E-mail address: tdhoward@wakehealth.edu 
 

 
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Organization: 
 
 
Wake Forest School of Medicine 
Statistician: 
 
 
Doug Case, Ph.D. 
 
 
 
Department of Biostatistical Sciences 
 
 
 
Division of Public Health Sciences  
 
 
Medical Center Boulevard 
 
 
Winston-Salem, NC 27157 
 
 
Telephone:  (336) 716-1048 
 
 
Fax:  (336) 716-6427 
 
 
E-mail address:  dcase@wakehealth.edu 
 
Organization: 
 
 
Wake Forest School of Medicine 
Statistician: 
 
 
Carl Langefeld, Ph.D. 
 
 
 
Center for Public Health Genomics 
 
 
 
Department of Biostatistical Sciences 
 
 
 
Division of Public Health Sciences  
 
 
 
Wake Forest School of Medicine 
 
 
Medical Center Boulevard 
 
 
Winston-Salem, NC 27157 
 
 
Telephone: (336) 716-1005 
 
 
E-mail address: clangefe@wakehealth.edu 
 
Grant: 
 
1UG1CA189824 (NCI) 
 
 
NCI/Division of Cancer Prevention 
 
 
Community Oncology & Prevention Trials Research Group 
 
 
9609 Medical Center Drive, Room 5E502 
 
 
Rockville, MD  20850 
 
 
(240) 276-7050 
 
 
2R25CA122061-07 (NCI) 
 
R21CA182111-01(NCI) 
 
 
 
Center for Integrative Medicine Pilot (Wake Forest) 
 
Participating Organizations: 
 
WAKE / Wake Forest NCORP Research Base: NCORP sites and WF 
affiliates 
 
Agent(s)/Supplier: 
  
N/A  
 
NCI Version Date: 
10/12/18 
 
 
WF IRB Amendment/Update # & Date: Amendment 2: 01/12/15 
 
 
Amendment 3: 03/05/15 
 
 
Amendment 4: withdrawn 
 
 
Amendment 5: 07/10/15 (staff change) 
 
 
Amendment 6: 08/31/15 
 
Amendment 7: 12/16/15 (consent change) 
 
Amendment 8: 12/29/15 (staff change) 
 
Amendment 9: 03/08/16 (staff change) 
 
Amendment 10: withdrawn 
 
Amendment 11: 04/20/16 (staff change) 
 
Amendment 12: 05/19/16 
 
Amendment 13: 12/07/17 
Amendment 14: 11/28/2018  
 
 
 

 
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RELAX – SCHEMA 
 
Pre-Screening 
After completion of all three screening questionnaires, participant must score accordingly on at 
least one questionnaire to be eligible:  
 
•score ≥8 on the anxiety subscale of the HADS 1 OR 
•score ≥4 on the Distress Thermometer 92-94 OR 
•score >5 on the 2-item screener from the Cancer Acceptance Scale 96 
 
 
Designated staff person at each site to enter data in the screening log for all potential 
participants screened (necessary for the Primary Study Aim examining feasibility).  
Randomization 
 
 
Stratification 
75 participants will be stratified by baseline self-reported dyspnea and randomized to 3 groups 
25 participants per Group:  
 
Group A:   The low-dose group will use the RESPeRATE device for 15 minutes once per 
day, at least 5 days per week for 12 weeks 
 
Group B:   The high-dose group will use the RESPeRATE device for 15-minute twice per 
day, at least 5 days per week for 12 weeks.  
 
Group C:  The usual breathing control group will use an identical control device (with 
nonrythmical tones that will not gradually slow down to reduce respiration rate) for 15 
minutes once per day, at least 5 days per week over 12 weeks. 
 
 
Intervention 
RESPeRATE device constantly synchronizes and automatically adjusts the melody/tones to the 
person’s breathing pattern to reduce breaths per minute by prolonging exhalation. It is the size 
of a portable compact disc player with a respiration sensor. Throughout the intervention, 
participants rate symptom intensity before and after using the devices.  
 
 
Baseline Data Collection 
Participants will be seen in clinic to receive their RESPeRATE device. The site coordinator will 
provide a demonstration on use of the device and assist participant with first use of the device. 
The following measures will be completed: Self-Reported Dyspnea, Spirometry (FEV1), 
Anxiety/Depression/Cancer-Related Worry, Fatigue, Cough Questionnaires, blood draw, and 
salivary cortisol collection. 
 
 
 
Weeks 1 – 11 Data Collection 
Site coordinators will contact participants on a weekly basis by phone to assess use of the 
device, answer questions, and collect breathing data for the prior 7 days stored on the device. 
 
 
Week 6 (mid-intervention) Data Collection   
In addition to the device breathing data, the following forms will be completed.by phone and/or 
mail. Brief questionnaires to include Self-Reported Dyspnea Anxiety/Depression/Cancer-
Related Worry, Fatigue, and Cough Questionnaires. 
 

 
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Week 12 Data Collection 
Participants will be seen in the clinic for collection of final breathing data and to complete 
measures: Self-Reported Dyspnea, Spirometry (FEV1), Anxiety/Depression/Cancer-Related 
Worry, Fatigue, Cough Questionnaires, blood draw, and salivary cortisol collection. Participants 
will return their RESPeRATE device to the site coordinator. 
 
 
Endpoints 
Feasibility (accrual, participation, adherence, retention), Anxiety, Cancer-Related Worry, Self-
Reported Dyspnea, Spirometry (FEV1), Epigenetic and Gene Expression Changes, salivary 
cortisol changes (for those who are eligible related to Supplemental Objective 1.5) 
 
Stratification: Site; Self-Reported Dyspnea 
Study Sample: 75 participants (25 per group) 
Study Duration: 12 weeks 
Brief Eligibility Criteria:  
 
Past History of any lung cancer 
 
For Stage I-III disease, patients should be 2-24 months post-completion of surgery, 
radiation therapy and/or chemotherapy with no further planned treatment during the 12-
week study and no evidence of disease. 
For Stage IV disease, patients may be receiving no treatment or may be receiving maintenance 
treatment with a target agent, chemotherapy, or immunotherapy provided the most recent imaging 
does not demonstrate progressive disease. 
 
After completion of all three screening questionnaires, participant must score accordingly 
on at least one questionnaire to be eligible: 
 
score ≥8 on the anxiety subscale of the HADS 1 OR  
 
score ≥4 on the Distress Thermometer 92–94  OR  
 
score >5 on the Modified Cancer Acceptance Scale 96 
 
Eastern Cooperative Oncology Group performance status 0-2 
 
*Note: Whole blood will be collected for DNA (for epigenetic analysis) and RNA (for gene 
expression analysis) isolation (at baseline and Week 12). These data will be used as preliminary 
data to indicate whether DNA methylation and/or gene expression variation correlates with 
changes in anxiety. This added genomics piece is a supplemental study objective and will 
capitalize on the larger parent RELAX trial. Twelve participants from each group will be required 
for analysis.  
                                                                         
The Screening Log should be completed on all potential participants. It is located in 
CCRBIS. Once logged in to CCRBIS, go to information, select protocol and then 
screening log.   
 
 
 

 
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TABLE OF CONTENTS 
 
 
COVER PAGE .......................................................................................................................... 1 
SCHEMA .................................................................................................................................. 4 
1. OBJECTIVES ...................................................................................................................... 7 
2. BACKGROUND................................................................................................................... 7 
3. SUMMARY OF STUDY PLAN ........................................................................................... 10 
4. PARTICIPANT SELECTION ............................................................................................ .10 
5. AGENT ADMINISTRATION .............................................................................................. 12 
6. DEVICE INFORMATION ................................................................................................... 13 
7. CLINICAL EVALUATIONS AND PROCEDURES .............................................................. 14   
8. PROTOCOL SPECIFIC TRAINING REQUIREMENTS ...................................................... 20 
9. SPECIMEN MANAGEMENT ............................................................................................. 20 
10.  REPORTABLE ADVERSE EVENTS/SERIOUS ADVERSE EVENTS .............................. 21 
11. STUDY MONITORING ...................................................................................................... 21 
12. STATISTICAL CONSIDERATIONS................................................................................... 23 
 
CONSENT  
 
REFERENCES 
 
APPENDICES: 
 
Appendix 1:     Data Submission Checklist 
Appendix 2:     Eligibility Checklist-Registration 
Appendix 3:     Pre-Screen Anxiety/Distress (Distress Thermometer, Modified Cancer 
Acceptance Scale, HADS-Anxiety/Depression)  
Appendix 4:     Cancer Dyspnea Scale (CDS) for Registration 
Appendix 5:     Current Medication Form 
Appendix 6:     Flow Sheet-Addenda 
Appendix 7:     Weekly Check-In Call/Data Capture from Device 
Appendix 8:     Participant Expectations 
Appendix 9:     Manchester Cough in Lung Cancer Scale  
Appendix 10:   PROMIS Fatigue  
Appendix 11:   Activities Form 
Appendix 12:   Pre-Screening Assent Form 
Appendix 13:   Visual Analogue Scales (VAS) for Distress Anxiety, and Dyspnea Pre- and 
Post-Session Ratings 
Appendix 14:   Device Instructions for Coordinators 
Appendix 15A:  Device Instructions for Participants - Blue 
Appendix 15B: Device Instructions for Participants – Green 
Appendix 15C: Device Instructions for Participants - Yellow 
Appendix 16:   Intervention Feedback 
Appendix 17:   Screening Log 
Appendix 18:   Saliva Collection Instructions and Diary 
Appendix 19:   RNA/DNA Lab Instructions 
Appendix 20:   Early Withdrawal Form 
Appendix 21:  Cancer Worry Scale 
 

 
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1. 
OBJECTIVES 
 
1.1. 
To assess feasibility (accrual, participation, adherence, retention) of a randomized study 
of device-guided breathing in 75 post-treatment lung cancer survivors with significant anxiety.  
 
1.2. 
To obtain preliminary data on the variability and efficacy of two doses of a device-guided 
breathing intervention versus a usual breathing control group for reducing anxiety (primary 
outcome) and for improving self-reported cancer-related worry,  dyspnea and respiratory 
functioning  (secondary outcomes) in post-treatment lung cancer survivors.  
    
1.3. 
To select the optimal dose of the device-guided breathing intervention (15 minutes 
once/day or twice/day) for subsequent randomized study.  
 
1.4. 
Supplemental Objective: To determine if changes in anxiety attributed to device-guided 
breathing are correlated with epigenetic (DNA methylation) and/or gene expression changes. 
 
1.5. 
Supplemental Objective: To obtain preliminary data on changes in salivary cortisol 
(diurnal slope, cortisol awakening response, area under the curve) in each intervention group 
and associations between salivary cortisol and anxiety.  
 
2. 
BACKGROUND 
 
2.1a 
Lung Cancer & Anxiety 
 
Psychological concerns are among the most commonly reported unmet needs among post-
treatment cancer survivors.6 Psychosocial distress, including anxiety and depressive symptoms, 
is also common.7,8 Up to 54% of post-treatment cancer survivors report clinically significant 
distress,9,10 which is associated with multiple adverse outcomes, including decreased quality of 
life (QOL),11–13 functional limitations,14,15 poor sleep,16,17 increased pain,18 and even increased 
mortality.19,20 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.21  The need for interventions to reduce psychosocial morbidity in post-treatment 
cancer survivors is critical.22,23 Psychosocial interventions for post-treatment cancer survivors 
may improve mental and physical health, potentially offsetting increased health care costs 
among distressed cancer survivors.24  
 
The number of lung cancer patients with improved prognosis who could benefit from symptom 
management interventions is likely to increase substantially with improved screening methods, 
demonstrating a 20% reduction in mortality.2 New clinical practice guidelines stemming from the 
National Lung Cancer Screening Trial (NLST) promoting lung cancer screening among high-risk 
groups3,4 will likely increase lung cancer screening and result in more survivors with improved 
survival after earlier diagnosis. If clinical patterns reflect trial data, we expect 57% (versus 15% 
currently) of those diagnosed after screening to have localized disease.2 An estimated 8.7 
million adults in the U.S. will be eligible for low-dose computed tomography (LDCT) screening 
according to NLST eligibility criteria,5 suggesting that the number of lung cancer patients will 
increase dramatically.  
 
Anxiety is a significant problem for a substantial minority of lung cancer survivors. Anxiety 
symptoms are common in post-treatment cancer survivors,6-10 significantly more so than pure 
depressive symptoms.11 Compared with other cancer types, lung cancer patients have the 
highest rates of psychological distress12 and report a higher number of unmet psychological 
needs, including fears of recurrence, physical disability or deterioration, difficulty making long-
term plans, feeling dependent and helpless, and preoccupation with being ill.13,14 Anxiety may 

 
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increase in the year after lung cancer surgery,15 and recent studies have reported rates of 
clinically significant anxiety among lung cancer patients and post-treatment survivors ranging 
from 20-30%.16-19  
 
Anxiety commonly co-occurs with distressing physical symptoms in patients with lung 
cancer.18,20,21 The correlation between self-reported anxiety and dyspnea is estimated at 0.3.21 
This relationship is bidirectional, reflecting affective and physiological processes.20,22-24 The 
number of lung cancer patients reporting dyspnea at some stage in their illness ranges from 55-
90%.20,21,25-27 Estimates of dyspnea in post-treatment ESLC survivors range from 40-60%.28,29 
Thus, dyspnea commonly occurs with anxiety after lung cancer treatment and is associated with 
worse functioning in multiple domains, greater distress, and lower quality of life.22,23,30-33  
 
Breathing interventions have been effective at reducing anxiety/distress in cancer patients. 
Interventions focused on slow, deep breathing have decreased anxiety, stress symptoms, and 
physiological arousal in clinical populations and healthy adults.34-37 Relaxation training is 
effective for relieving anxiety in cancer patients.8,10 Breathing interventions have been 
incorporated into interventions to address dyspnea and related distress in lung cancer 
patients.38 Few studies have examined concomitant changes in anxiety/distress, and anxiety 
level has not been a criterion for study entry. Such multi-component interventions have yielded 
promising results for anxiety and distress related to breathlessness in post-treatment lung 
cancer survivors.39,40 
 
2.1b 
Background for Supplemental Objective: Epigenetic Changes & Anxiety 
 
A number of recent studies have reported epigenetic changes associated with mental health 
and mood disorders. These have included post-traumatic stress disorder 81, depression 82, and 
suicide 83, and provide support for our hypothesis that epigenetic variation also contributes to 
changes in anxiety levels. Taken together, epigenetic variation in a number of individual genes 
and biological pathways has been identified for these conditions, and include inflammatory 82 
and immune 81 related genes, as well as genes involved in the hypothalamic-pituitary-adrenal 
(HPA) axis. 84 
 
2.1c 
Background for Supplemental Objective: Cortisol Changes & Anxiety 
 
Cortisol is a glucocorticoid and a biomarker of stress that is released from the hypothalamic 
pituitary adrenal (HPA) axis.85, 87 Studies within the psychoneuroendocrinology literature have 
demonstrated a relationship between psychological distress and cortisol response. For 
example, studies have demonstrated an association between cortisol and depressive 
symptoms, 86,87post-traumatic stress disorder symptoms, 88 and anxiety. 89 Additionally, other 
similar psychosocial interventions have demonstrated changes in cortisol response. 90,91  
Collectively, these studies support our hypothesis that changes in anxiety, attributed to the 
device-guided breathing, will be associated with changes in cortisol response.    
 
Participants with endocrine disorders (e.g., diabetes and thyroid disorders) or on steroid-based 
medications are excluded from the cortisol portion of the study (with the exception of topical 
steroid creams/ointments which are permitted). 
 
2.2  
Study Intervention 
 
The RESPeRATE device constantly synchronizes and automatically adjusts the melody/tones to 
the person’s breathing pattern to reduce breaths per minute by prolonging exhalation. It is the 
size of a portable compact disc player with a respiration sensor (attached to an elastic belt worn 
over clothing) and a pair of headphones. The device is easy to use, and pilot participants have 

 
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found it appealing. In our pilot work and other studies, attrition rates have been low,41 and 
adherence to the recommended rate of use has been high.42-44  
 
For the low-dose group, participants will use the RESPeRATE device for 15 minutes once a 
day, at least 5 days a week for 12 weeks based on previous research that found this dose to be 
effective in reducing blood pressure.45-47 For the high-dose group, participants will use the 
RESPeRATE machine in 15-minute increments twice a day, at least 5 days a week for 12 
weeks, similar to the dose used in previous research conducted with other clinical populations 
with significant respiratory symptoms.48,49 An effective rate of slow breathing is considered to be 
<10 respirations/minute.42 The device automatically records use (i.e., accumulated duration, 
number of times used, average duration), initial breathing rate, and final breathing rate. This 
information will be used to measure intervention adherence.  
 
2.3  
Rationale for Intervention & Control Conditions 
 
Device-guided breathing has not been studied in lung cancer survivors, yet it shows promising 
results in patients with chronic medical conditions and anxiety disorders. We propose use of a 
low-cost biofeedback device called RESPeRATE that can be used at home and guides patients 
to reduce their respiration rate and increase exhalation time. RESPeRATE has FDA approval as 
an adjunctive treatment for hypertension. Positive outcomes, including improved 
cardiorespiratory fitness and quality of life, have been observed in heart failure patients, 
particularly in groups receiving longer treatment and in participants who were successful at 
increasing their inhalation/exhalation ratio.48,49 These studies did not assess anxiety or other 
psychological outcomes. A similar biofeedback device used in a single-arm pilot study for 
outpatients with anxiety disorders yielded significant reductions in anxiety and increased levels 
of relaxation,50 suggesting that this approach is promising for reducing clinically significant 
anxiety symptoms.  
 
Despite high rates of psychological distress, no behavioral interventions identified in a recent 
meta-analysis specifically targeted lung cancer survivors, and very few (8%) were conducted 
with any post-treatment survivors.8,51 Research has identified the time after lung cancer 
treatment as particularly challenging, with reports of increased anxiety and uncertainty about the 
future.52 Intervening with post-treatment lung cancer survivors with significant anxiety is 
important because psychological symptoms may receive less attention when contact with 
providers is less frequent. A recent review of psychosocial oncology interventions reported that 
only 5% of psychosocial oncology intervention studies addressed patients with significant 
distress,51 even though high distress patients are most likely to benefit.53 
 
The device-guided breathing intervention can be easily implemented at home with minimal 
instruction. This intervention could make behavioral treatments for anxiety more accessible to 
rural cancer survivors who experience mental health issues (including anxiety) at 
disproportionately higher rates than non-rural survivors 54,55 and often lack access to mental 
health professionals. 51,55-58 It could also be broadly applied in community-based cancer 
survivorship settings. 
 
The proposed device-guided breathing intervention works by gradually slowing the respiration 
rate. Slow, deep breathing enhances parasympathetic tone, decreases acute and chronic 
sympathetic arousal, and reduces excitatory nervous activity, likely through cellular signaling 
activated by stretch receptors in the lungs.59  
 
The relaxation response occurs acutely, but indicators of chronic sympathetic over-activation, 
such as resting hypertension, also decrease. Deep breathing improves respiratory and 
cardiovascular function, decreases effects of stress, and improves mental health.1 Disordered 

 
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respiration is thought to be a key aspect of anxiety and stress-related disorders,34,37 thus slow 
breathing also reduces anxiety and potentially dyspnea.60,61 
 
Participants in the usual breathing control group will use an identical-looking device but only the 
RESPeRATE intervention is targeted at reducing respiration rate. The chimes for the control 
device will be nonrythmical tones that will not gradually slow down to reduce respiration rate.  A 
similar control device is available from the same company and has been employed in other 
studies of the RESPeRATE device. 104  
 
3. 
SUMMARY OF STUDY PLAN 
 
The RESPeRATE device constantly synchronizes and automatically adjusts the melody/tones to 
the person’s breathing pattern to reduce breaths per minute by prolonging exhalation. It is the 
size of a portable compact disc player with a respiration sensor. 
 
This pilot study will have three groups: RESPeRATE device-guided breathing group (low-dose) 
(n=25), RESPeRATE device-guided breathing group (high-dose) (n=25), and a usual breathing 
control group (n=25).  
 
The low-dose group will use the RESPeRATE device for 15 minutes once per day, at least 5 
days per week for 12 weeks. 
  
The high-dose group will use the RESPeRATE device for 15-minutes twice per day, at least 5 
days per week for 12 weeks.  
 
The usual breathing control group will use an identical control device (with nonrythmical tones 
that will not gradually slow down to reduce respiration rate) for 15 minutes once per day, at least 
5 days per week over 12 weeks. 
 
After randomization, participants will be introduced to their assigned device and receive 
instructions and a demonstration on use. Participants will use the device at least 5 days per 
week for the assigned amount of time over 12 weeks.   
 
All participants will complete pre- and post-intervention questionnaires spirometry (FEV1) at 
baseline and Week 12, weekly telephone contact to provide breathing data for the prior 7 days, 
brief mid-intervention questionnaires (at Week 6), and rate symptom intensity while using the 
devices (before and after one session each week). Eligible participants will collect salivary 
cortisol samples for three days following the baseline and Week 12 follow-up. Participants will 
have a blood draw at the baseline and Week 12 visits to determine if RNA and/or DNA 
methylation and/or gene expression variation correlates with anxiety changes. The duration of 
the study is 12 weeks. 
 
Participants will be stratified by baseline self-reported dyspnea score and assigned with equal 
probability to either intervention group or the control group using variable length permuted block 
randomization. Block sizes will be chosen randomly to ensure that future assignments cannot 
be inferred from previous ones.   
 
Drs. Danhauer and Weaver will meet with designated staff members from each NCORP site for 
a training session to review the protocol and provide intervention information. This training will 
take place at the annual meeting of the WF NCORP RB and/or at individual sites, as needed.  
 
 
4. 
PARTICIPANT SELECTION 
 

 
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4.1. 
Inclusion Criteria 
 
4.1.1 Past History of any lung cancer 
 
4.1.2 For Stage I-III disease, patients should be 2-24 months post-completion of surgery, 
radiation therapy and/or chemotherapy with no further planned treatment during the 12-week 
study and no evidence of disease. 
 
4.1.3 For Stage IV disease, patients may be receiving no treatment or may be receiving 
maintenance treatment with a target agent, chemotherapy, or immunotherapy provided the most 
recent imaging does not demonstrate progressive disease. 
 
4.1.4 After completion of all three screening questionnaires, participant must score accordingly 
on at least one questionnaire to be eligible:  
 
 
Score ≥ 8 on the anxiety subscale of the HADS-Anxiety/Depression Scale1 OR  
 
Score ≥ 4 on the Distress Thermometer92–94 OR 
 
Score > 5 on the Modified Cancer Acceptance Scale 96  
 
4.1.5 Eastern Cooperative Oncology Group performance status 0-2 
 
4.1.6 Willing/able to attend brief introductory session and use assigned device for the 
assigned period of time (15 minutes once or twice per day), at least 5 days per week for 12 
weeks  
 
4.1.7  Age ≥ 18 years 
 
4.1.8  Must have telephone 
 
4.2  
Exclusion Criteria 
 
 
 
4.2.1 Patient does not understand English 
 
4.2.2 Active lung infection 
 
4.2.3 Progressive cancer (must be considered no evidence of disease or stable) 
 
4.2.4 Any change in psychotropic medications in past 30 days 
 
4.2.5 Hearing loss that would preclude participating in interventions.  Adequate hearing to 
participate will be determined via: (1) Response of “no” to the question [“Do you have a hearing 
problem now?”] Participants with hearing aids will be allowed to enroll as long as their hearing is 
adequate to hear the sounds on the study devices. If necessary, potential study participants will 
receive a brief test trial with the RESPeRATE device. If they indicate inability to hear the guiding 
tones, they will not be enrolled in the study.   
 
Cortisol Exclusion 
 
4.2.6. Participants with endocrine disorders (e.g., diabetes and thyroid disorders) or on steroid-
based medications are excluded from the cortisol portion of the study (with the exception of 
topical hydrocortisone that is permitted).  
 

 
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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. 
 
Race/Ethnicity 
 
Gender 
White, not 
of 
Hispanic 
Origin 
Black, not 
of 
Hispanic 
Origin 
 
Hispanic 
Asian or 
Pacific 
Islander 
 
Unknown 
 
Total 
Male 
 
35 
8 
1 
1 
0 
45 
Female 
 
25 
4 
1 
0 
0 
30 
Total 
 
60 
12 
2 
1 
0 
75 
 
4.4 
Recruitment and Retention Plan   
 
We plan to recruit 75 lung cancer survivors through the WF NCORP RB.  We anticipate that 
each participating site should be able to accrue one participant every 1-2 months for a total of 6-
12 participants per site per year.  Thus, with at least 12 study sites, we should finish accrual in 
approximately 12 months. 
The WF NCORP RB sites will accrue to this trial. The WF NCORP RB has infrastructure in 
place to conduct the trial, including a web-based, interactive database for online participant 
registration and data management. 
 
Potential participants may be recruited via (1) identifying lung cancer survivors through the site 
cancer registry; (2) in-clinic screening during medical appointments; (3) screening clinic charts; 
and (4) patient recruitment posters and recruitment letters. 
Survivors will be approached in-person or by telephone by NCORP staff to ascertain interest 
and initial eligibility. We will track numbers of lung cancer survivors approached and screened, 
reasons for nonparticipation, and number randomized. 
 
We have targeted a racial/ethnic minority recruitment goal per the table above (consistent with 
national rates of lung cancer). 76 To reach this goal we will use several strategies: (1) We will 
work directly with oncology nurse navigators at each site to ensure that our clinic referrals 
include eligible minority patients and to enlist assistance in recruiting these patients. Their 
trusted relationships with  our lung cancer patients will lend credibility to our participation 
request and commitment to protect confidentiality; and (2) We will attempt to recruit all 
potentially eligible minority lung cancer survivors identified through institutional cancer registries, 
but whom we cannot recruit in person or via another medical center provider, by direct mail or 
phone. We will review our mailed recruitment materials to ensure that they are at an appropriate 
literacy level and are appealing to minority participants.  
 
5. 
AGENT ADMINISTRATION                   
 
See Section 8. Protocol Specific Training Requirements 
 
5.1 
Adherence/Compliance 

 
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5.1.1 Adherence will be calculated as the actual amount of time the device is used divided by 
the prescribed time. Successful adherence will be defined as use of the device ≥75% of the time 
assigned. Note that all participants will be included in the primary analyses, regardless of 
adherence. A secondary analysis will include only those participants who were at least 75% 
adherent. 
 
5.1.2 To determine intervention adherence, the RESPeRATE device tracks the number and 
duration of device uses and initial and final respiration rates. 
 
6. 
DEVICE INFORMATION 
 
6.1 
 Availability 
 
The RESPeRATE devices are easily available and do not require any sort of prescription or 
permission to purchase. 
 
6.2 
Device Request and Distribution for Sites 
 
Devices will be distributed to the sites from Wake Forest NCORP Research Base when the 
study is IRB approved at their site. Upon completion of the last participant, the site will return the 
RESPeRATE devices to the Wake Forest NCORP Research Base. See Section 6.6 for more 
information.           
 
6.3 
Device Accountability 
 
Not applicable. The intervention is a simple and publicly available device. It is not a drug agent. 
 
6.4  
Registration/Randomization 
 
6.4.1 Registration Process     
 
An IRB letter of approval and an IRB approved consent form must be received by the Research 
Base Protocol Information Office – Attn:  Site Coordinator prior to patient registration. Fax: (336) 
716-6275 
 
Fill out Appendix 2, Eligibility Checklist / Registration Form, and use this to complete the online 
registration. 
 
Online Registration 
 
NCORP site staff will register their study participants into the WF NCORP RB database by 
following the instructions below: 
 
Log on to the WF NCORP Research Base registration web site at 
https://ccrbis.phs.wakehealth.edu.  Enter your username and password (which may be obtained 
by contacting Robin Rosdhal RN OCN at rosdhal@wakehealth.edu).  In the “Patient 
Registration and Protocol Information” table, click “Register Patient/Patient Info” with the 
corresponding protocol number found in the drop-down box to the right. Fill in the eligibility 
criteria forms using the drop-down boxes.  If further information is needed by Data 
Management, they will contact you. Once the patient information has been entered online, print 
a copy of the eligibility checklist/registration form for your records. Press the submit button and 
a confirmation page will appear.  Print this confirmation sheet for your records.  The WF 

 
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NCORP Research Base Online Protocol Registration/Eligibility form, initial flow sheet, signed 
consent, histology reports, scan reports and lab reports (as required in protocol) should be 
faxed to (336) 713-6476 or mailed to Data Management: 
 
Wake Forest School of Medicine  
Department of Social Sciences and Health Policy 
WF NCORP Research Base 
Data Management Center 
525 @ Vine, 4th Floor 
P.O. Box 573152 
Medical Center Boulevard 
Winston-Salem, NC 27157-3152 
 
These forms should be retained in the patient’s study file. These forms will be evaluated during 
an institutional WF NCORP Research Base site member audit. 
 
If you have questions related to the registration process or require assistance with registration, 
please contact the WF NCORP Research Base DMC between 8:30am and 4:00pm EST, 
Monday through Friday at (336) 713-3172 or 713-6507. 
 
6.4.2 Randomization Process 
 
Patients will be stratified by baseline dyspnea score (Cancer Dyspnea Scale score ≥ 8 v. < 8; 
see Table 7.8) and assigned with equal probability to either RESPeRATE intervention group or 
the control group using variable length permuted block randomization. Block sizes will be 
chosen randomly to ensure that future assignments cannot be inferred from previous ones.  
Patients need to report a minimum level of clinically significant anxiety symptoms (HADS-
Anxiety/Depression Scale anxiety subscale ≥ 8), cancer-related worry (Modified Cancer 
Acceptance Scale score > 5), or distress (Distress Thermometer ≥ 4) to enter the study. 
 
6.5 
Unblinding Methods  
 
Not applicable. 
 
6.6 
Device Return 
 
Study participants will return any study devices to the site that issued them. All sites must return 
study devices to the Wake Forest NCORP Research Base at the following address:  
 
Robin Rosdhal, RN, OCN 
Wake Forest School of Medicine 
Department of Social Sciences and Health Policy 
NCORP Research Base – 525@Vine, 4th floor 
P.O. Box 573152 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
7. 
CLINICAL EVALUATIONS AND PROCEDURES 
 
7.1 
Schedule of Events 
 

 
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Participants will be randomized to one of three groups: RESPeRATE device-guided breathing 
group (low-dose) (n=25), RESPeRATE device-guided breathing group (high-dose) (n=25), and 
a usual breathing control group (n=25).  
 
The low-dose group will use the RESPeRATE device for 15 minutes once a day, at least 5 days 
per week for 12 weeks. 
  
The high-dose group will use the RESPeRATE device for 15-minutes twice a day, at least 5 
days per week for 12 weeks.  
 
The usual breathing control group will use an identical control device (with nonrythmical tones 
that will not gradually slow down to reduce respiration rate) for 15 minutes once per day, at least 
5 days per week over 12 weeks. 
 
After randomization, participants will be introduced to their assigned device and receive 
instructions and a demonstration on use. Participants will use it at least 5 days per week for the 
assigned amount of time over 12 weeks. All participants will complete pre- and post-intervention 
questionnaires, spirometry (FEV1) at baseline and Week 12, weekly telephone contact to 
provide breathing data for the prior 7 days, brief mid-intervention questionnaires by mail with a 
stamped return envelope enclosed and/or telephone contact at Week 6, and rate symptom 
intensity while using the devices (before and after one session per week). Eligible participants 
will collect salivary cortisol samples for three days following baseline and the Week 12 follow-
up. Participants with endocrine disorders (e.g., diabetes and thyroid disorders) or on steroid-
based medications (topical steroid medications are permitted) are excluded from the cortisol 
portion of the study.  Participants will have a blood draw at the baseline and 12 week visits, to 
determine if RNA and/or DNA methylation and/or gene expression variation correlates with 
anxiety changes. The duration of the study is 12 weeks. 
  
The NCORP staff member will instruct each participant in use of the RESPeRATE device at 
baseline. Participants will be told that RESPeRATE analyzes a person’s breathing pattern and 
plays 2 distinct tones that guide the person to inhale and exhale. The RESPeRATE control 
device looks and sounds identical but is not programmed to gradually slow breathing rate as in 
the active intervention arm. All participants will be provided with written instructions for the 
assigned device and will be observed using the device during the visit. To enhance adherence, 
we will have a NCORP staff member call participants  weekly to assess experience with the 
device, troubleshoot difficulties that may have arisen and obtain breathing data for the prior 7 
days. Participants who have not been using the device at the recommended frequency will 
troubleshoot ways of overcoming barriers to adherence as needed. 
 
Self-reported dyspnea and spirometry (FEV1) include questionnaires and a pulmonary function 
test (PFT). These measures will be administered in-person at the NCORP site during baseline 
and post-intervention (Week 12) assessments. A shorter battery will be administered mid-
intervention via mailed paper questionnaire with a stamped return envelope enclosed (Week 6). 
Any serious adverse event grade 4 or 5 related to the intervention will be reported to the WF 
NCORP RB at the time they become known to the NCORP site. (See Section 10.0) 
 
7.2 
Pre-Screening Evaluation/ Baseline Testing 
 
 
Pre-Screening: 
 
A minimal score on one of three measures is required for study eligibility. These measures 
include: (1) Score > 5 on the Modified Cancer Acceptance Scale (two-item screener) OR (2) 

 
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Score ≥ 4 on the Distress Thermometer OR (3) Score of ≥ 8 on the anxiety subscale of the 
HADS-Anxiety/Depression Scale.   
 
 
The single-item Distress Thermometer is a brief, single-item screening tool 
assessing distress from 0 (no distress) to 10 extreme distress). Recent meta-
analyses have identified a score ≥ 4 as an appropriate cut-off for identifying 
significant levels of distress.  
 
The Modified Cancer Acceptance Scale assesses fear of disease recurrence and 
consists of 2 items: ‘‘I worry about the cancer returning’’ and ‘‘I am anxious about my 
health.’’ Both items are rated on a 4-point Likert scale ranging from ‘‘does not apply 
to me at all’’ to ‘‘completely applies to me.’’ Scores range from 2 to 8. 
 
The full HADS (including the depression subscale) will be administered either over 
the phone or in person. Scores will be used as the baseline value to minimize burden 
by administering the measure again within a short time interval. The HADS-
Anxiety/Depression Scale is a 14-item self-report measure that is scored by 
assigning a numeric value to each of the 14 items (0, 1, 2, or 3), and then totaling 
item scores.  The minimum score is 0 and the maximum score is 42.  Anxiety and 
depression subscales each consist of the sum of 7 questions (range 0-21 for each 
subscale).  A score > 8 on the anxiety subscale indicates significant anxiety.  Some 
items may be left blank.  In this case, scores will be calculated as long as more than 
half the items are answered.  The scores will be calculated as the mean of the 
responses times the number of items in the scale (7 for the subscales and 14 for the 
overall scale). 
 
Eastern Cooperative Oncology Group performance status 0-2. 
 
Baseline testing: 
 
 
Hospital Anxiety/Depression Scale (HADS)  (use form completed for screening) 
 
Cancer Worry Scale 
 
Cancer Dyspnea Scale (CDS) will be needed for registration 
 
PROMIS Fatigue  
 
Manchester Cough in Lung Cancer Scale 
 
Activities form 
 
Current medications 
 
Participant expectations rating 
 
Spirometry (forced expiratory volume in one second [FEV1]) 
 
Visual Analogue Scales (VAS) for distress, anxiety and dyspnea—this form should 
be completedonce a week before and after a single use of the device during Weeks 
1-12  
 
Blood draw—a blood sample of approximately 2 teaspoons will be taken from a vein 
in the arm/central line for DNA methylation levels and RNA. 
 
Salivary cortisol collection—saliva samples will be collected by participants at time of 
awakening, 30 minutes post-awakening, and at bedtime for three consecutive days 
(9 samples per participant). 
 
7.3 
 Evaluations during Study Intervention at Weeks 1 - 11 
 
Weeks 1 - 11:  
 
Weekly Check-in Call/Data Capture from Device via telephone interview.  The 
participant will be contacted by phone to assess his/her experience with the device 
and troubleshoot difficulties that may have arisen and obtain breathing data for the 
prior 7 days. The participant will also be asked if (s)he completed the once weekly 

 
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VAS for distress, anxiety, and dyspnea (before and after a single use of the device 
each week). If (s)he has not done so, (s)he will be asked to complete the VAS form 
before and after their next use of the device. Participants who have not been using 
the device at the recommended frequency will troubleshoot ways of overcoming 
barriers to adherence, as needed. 
 
Week 6:  
 
In addition to phone contact, participants are to complete the following 
questionnaires (may be done via mail): 
 
Hospital Anxiety/Depression Scale (HADS)   
 
Cancer Worry Scale 
 
Cancer Dyspnea Scale 
 
PROMIS Fatigue 
 
Manchester Cough in Lung Cancer Scale 
 
Activities form 
 
Weekly Check-in Call/Data Capture from Device Form (via telephone) 
 
7.4 
Evaluations at Completion of Study Intervention 
 
Week 12: 
 
Hospital Anxiety/Depression Scale (HADS) 
 
Cancer Worry Scale 
 
Cancer Dyspnea Scale (CDS) 
 
PROMIS Fatigue  
 
Manchester Cough in Lung Cancer Scale 
 
Activities form 
 
Current medications 
 
Collect Weekly Check-In Call/Data Capture from Device forms 
 
Intervention feedback 
 
Spirometry (forced expiratory volume in one second [FEV1]) 
 
Visual Analogue Scales (VAS) for distress anxiety and dyspnea  
 
Blood draw—a blood sample of approximately 2 teaspoons will be taken from a vein 
in the arm/central line for DNA methylation levels and RNA.  
 
Salivary cortisol collection, if applicable—saliva samples will be collected by 
participants at awakening, 30 minutes post-awakening, and at bedtime for three 
consecutive days (9 samples per participant) 
 
7.5   
Methods for blood draw and transport 
 
7.5.1 For detection of DNA methylation levels:  
Genomic DNA will be isolated from whole blood (one 8/8.5 ml yellow-top, ACD tube).  DNA will 
be isolated using the AutoPure LS (Qiagen, Inc.), and then bisulfite-converted using the EZ 
DNA Methylation Gold kit (Zymo, Irvine, CA). To determine the proportion of DNA methylation at 
each of over 485,000 CpG sites, we will use the HumanMethylation450 BeadChip (Illumina, 
Inc.) along with the iScan Reader (Illumina, Inc.). 
 
7.5.2. RNA: 
RNA will be isolated from whole blood collected in one 2.5/4 ml tube using the PAXgene Blood 
RNA System (Qiagen), following the manufacturer’s instructions. The PAXgene system 
stabilizes the RNA and minimizes degradation, a process that can lead to false results in 

 
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subsequent analysis. As with the DNA, the whole blood for RNA will be stored with the tube 
upright at room temperature until transported to the laboratory. RNA will be isolated with the 
PAXgene Blood RNA System (Qiagen), following the manufacturer’s instructions. Once isolated, 
RNA will be evaluated for quality and quantity using the RNA 6000 Nano chips and analyzed on 
the Agilent 2100 Bioanalyzer (Agilent Techonology, Inc). Expression profiles will be generated 
with HumanHT-12 v4 Expression BeadChips (Illumina, Inc.), which assay over 47,000 probes 
spanning approximately 30,000 genes. BeadChips will be scanned with the iScan Reader 
(Illumina, Inc.), and preliminary analysis will be performed with Genome Studio (Illumina, Inc.).   
 
Blood samples will be collected at baseline and Week 12.  Once collected, Dr. Timothy Howard’s 
lab will be notified by phone at (336) 713-7509. Samples will be processed and shipped per 
instructions in Appendix 19. 
 
7.5.3. Methods for cortisol collection, assays, and mailing: 
Participants with endocrine disorders (e.g., diabetes and thyroid disorders) or on steroid-based 
medications (topical steroid medications are permitted) are excluded from the cortisol portion of 
the study. 
 
Materials for saliva collection will be distributed to participants at baseline.  Materials can be 
provided in-person at the clinic visit or the materials can be shipped to the participant’s home.  
Participants will collect saliva samples three times a day (at awakening, 30 minutes post-
awakening, and bedtime) for three consecutive days following baseline and three consecutive 
days following the Week 12 follow-up visit. Saliva samples are collected by placing a cotton roll 
under the tongue for approximately 1-2 minutes which is subsequently stored in a plastic tube 
and refrigerated. Participants will be instructed to refrain from eating, drinking, smoking, 
brushing their teeth, using mouthwash, or engaging in exercise or similar physical activity for 30 
minutes prior to saliva collection. Participants will be provided with saliva collection diaries to 
record compliance to these behaviors as well as the time in which their saliva samples were 
collected. After all nine samples have been collected at each time point (baseline, Week 12 
follow-up), participants may return their samples and saliva collection diaries by: 1) returning 
them to the local clinic within 2 weeks of collection and the local clinic will take responsibility for 
sending them to Wake Forest NCORP Research Base, or 2) using pre-paid postage to return 
their samples and saliva collection diaries directly to the Wake Forest NCORP Research Base. 
Once received at the Wake Forest NCORP Research Base, all samples will be refrigerated (-
80 C) until assayed. 
Samples will be assayed in duplicate at Wake Forest NCORP Research Base using The 
Salimetrics® Cortisol Enzyme Immunoassay Kit (State College, PA). At no time in the testing 
process are samples identified by name of subject or any information that would link the sample 
directly to an individual. On the day of analysis, samples are thawed at room temperature (20 to 
22°C), centrifuged (1500 x g) for 15 minutes and assayed. The test used 25 μL of saliva per 
determination, has a lower limit of sensitivity of 0.003 μg/dL, standard curve range from 0.012 
μg/dL to 3.0 μg/dL, an average intra-assay coefficient of variation of 3.5% and an average inter- 
assay coefficient of variation of 5.1%. Method accuracy determined by spike and recovery 
averaged 100.8% and linearity determined by serial dilution averaged 91.7%. Values from 
matched serum and saliva samples show the expected strong linear relationship, r (47) = 0.91, 
p < 0.0001. 
Samples are returned to the freezer upon completion of pipetting. Assay data are reviewed by 
the supervisor and samples needing to be retested are identified. Samples needing retesting 
are again thawed, analyzed and refrozen. After assays are complete, samples will be stored for 
up to 60 days and then disposed of per applicable waste handling regulations.   

 
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7.6  
Post-intervention Follow-up Period – N/A 
 
7.7  
Methods for Clinical Procedures – N/A 
7.8 
Study Parameter Table 
 
Pre- 
Screen 
 
Screen 
 
Baseline 
 
Week 1 
 
Week 6  
 
Week 12 

 
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(A) Designated staff person at each site will log-in to CCRBIS to enter data in the screening log 
for all potential participants screened (necessary for the Primary Study Aim examining 
feasibility). 
Consent 
 
X 
 
 
 
 
Flow Sheet 
 
 
X 
 
X 
X 
Screening Form (A) 
(To be completed on eligible and ineligible patients that 
do not want to participate) 
 
X 
 
 
 
 
HADS-Anxiety/Depression Scale 64-66, 68-70 
(pre-screen if done by phone in advance OR at baseline 
if done in person). 
     X (C) 
 
 
 
 
X 
X 
Distress Thermometer (1 item) 
 
X 
 
 
 
 
 
Modified Cancer Acceptance Scale (2 items) 
 
X 
 
 
 
 
 
Cancer Worry Scale (8 items) 95 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
Spirometry (FEV1) 
 
 
X 
 
 
X 
Cancer Dyspnea Scale (CDS) 62, 63, 67, 73 
Will be needed for registration 
 
 
     X (D) 
 
 
X 
X 
PROMIS Fatigue 79 
 
 
X 
 
 
X 
X 
Manchester Cough in Lung Cancer Scale 80 
 
 
X 
 
 
X 
X 
Activities Form  
 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
Current Medications 
 
 
X 
 
 
X 
Weekly Check-In Call/Data Capture from Device 
(via telephone interview) 
 
 
X 
Weekly (1-12) 
Participant Expectations 74, 75 
 
 
X 
 
 
 
 
Intervention Feedback  
 
 
 
 
 
X 
Early Withdrawal Form 
 
If patient withdraws prior to completion of study. 
RNA/DNA Labs   
 
 
X 
 
 
X 
Salivary cortisol collection (B) 
 
 
X 
 
 
X 
 
** Visual Analogue Scales for Distress, Anxiety, and 
Dyspnea 71, 72 
 
 
Should be requested by mail and submitted at Week 6 and at 
completion of the Week 12 study.  
 
Completed before and after a single use of the device each week 
during Weeks 1-12. 
 
(Participant will need several double sided forms) 
 1 selected use/week x 12 weeks = 12 forms 
 
 

 
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(B) *Participants with endocrine disorders (e.g., diabetes and thyroid disorders) or on steroid-
based medications are excluded from the salivary cortisol portion of the study.  Topical 
steroid medications (creams/ointments) are permitted 
(C) Pre-screen HADS may be used for baseline and does not need to be repeated.  
(D) CDS will need to be collected prior to registration 
  
 
7.9  
Off Treatment Criteria  
 
Participants may stop using the device for the following reasons: completed the protocol-
prescribed intervention, adverse event or serious adverse event, inadequate device functioning, 
noncompliance, or medical contraindication.   
Participants will continue to be followed, if possible, for safety reasons and in order to collect 
endpoint data according to the schedule of events.  Participants will not be replaced for 
discontinuing the device. 
7.10 
Off Study Criteria 
 
Participants may go “off-study” for the following reasons: the protocol intervention and any 
protocol-required follow-up period is completed, adverse event/serious adverse event, lost to 
follow-up, non-compliance, concomitant medication, medical contraindication, withdraw consent, 
or death.   
We anticipate an approximate 20% attrition rate, and the total sample size has been adjusted 
accordingly.   
8. 
PROTOCOL SPECIFIC TRAINING REQUIREMENTS 
 
8.1 
Specific Training Procedures or Certification Procedure 
 
Several methods will be used in training sites.  A training session will be held at the annual 
Research Base meeting and/or other meetings as designated by Drs. Danhauer and Weaver. 
 
9. 
SPECIMEN MANAGEMENT   
 
  
9.1  
Blood for Research Testing  
 
Blood samples will be shipped and stored with a unique identifier and will not include any 
information protected by HIPAA regulations. Storage for blood samples is located at Wake 
Forest University Baptist Medical Center.  
 
Center for Genomics & Personalized Medicine Research 
Wake Forest School of Medicine 
NRC Bldg., Room 319 
Medical Center Blvd. 
Winston-Salem, NC 27157 
Phone: (336) 713-7509 
 
(See Appendix 18 and 19 for further lab instructions.) 
 
After study-related tests have been performed, blood samples/blood derivatives (serum, 
plasma, PBMCs and their derivatives) are returned to the freezer. Samples will be stored for up 
to 60 days to allow assay data to be reviewed by the supervisor and samples needing to be 

 
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retested identified. Samples needing retesting are again thawed, analyzed and refrozen. After 
assays are complete, samples will be disposed of per applicable waste handling regulations.   
 
 
10 
REPORTABLE ADVERSE EVENTS/SERIOUS ADVERSE EVENTS 
 
Only report unexpected serious adverse events, Grades 4 and 5, which are related to the use 
of the breathing device used in this study.  
 
Adverse Event/Serious Adverse Event reporting begins after the informed consent is signed. 
Serious Adverse Events occurring within 30 days of study completion must be reported via FDA 
Form 3500 (MedWatch).  
 
11. 
STUDY MONITORING 
 
11.1 
Data Management Schedule 
 
The Eligibility checklist/Registration Form should be completed on-line prior to placing the 
patient on study. Data forms will be submitted to the WF NCORP Research Base.  See Section 
6.4.1 for mailing address, or fax to (336) 713-6476.  
Form 
Submission Schedule 
HADS Form 
Within 14 days of Pre-Screen or 
Baseline, Week 6, Week 12 
Distress Thermometer  
Within 14 days of Pre-Screen 
Modified Cancer Acceptance Scale  
Within 14 days of Pre-Screen 
Cancer Worry Scale  
Within 14 days of Baseline, Week 6, 
Week 12 
Informed Consent 
Within 14 days of Baseline 
Cancer Dyspnea Scale (CDS) 
Within 14 days of Baseline, Week 6, 
Week 12 
Flow Sheet/Addenda 
Within 14 days of Baseline, Week 6, 
Week 12 
Current Medications 
Within 14 days of Baseline, Week 12 
Participant Expectations 
Within 14 days of Baseline 
PROMIS Fatigue   
Within 14 days of Baseline, Week 6, 
Week 12 
 Manchester Cough in Lung Cancer Scale  
Within 14 days of Baseline, Week 6, 
Week 12 
Activities Form 
Within 14 days of Baseline, Week 6, 
Week 12 
Weekly Check-In/Call Data Capture from Device 
Within 14 days of Week 6, Week 12 
Visual Analog Scales 
Within 14 days of Week 6, Week 12 
RNA/DNA Lab Sample Form 
Within 14 days of Baseline, Week 12 
Intervention Feedback 
Within 14 days of Week 12 
Early Withdrawal Form 
Within 14 days of Upon withdrawal from 
active treatment or consent 
Screening Form (Eligible and Ineligible participants) ** 
Monthly 
** Designated staff person at each site will log-in to CCRBIS to enter data in the 
screening log for all potential participants screened (necessary for the Primary Study 
Aim examining feasibility). 
 
11.2 
Case Report Forms 
 
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11.3 
Source Documents 
 
Source documents are the original signed and dated records of participant information (e.g., the 
medical record, shadow chart) which may include electronic documents containing all the 
information related to a participant’s protocol participation. Source documents are used to verify 
the integrity of the study data, to verify participant eligibility, and to verify that mandatory 
protocol procedures were followed. 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 or 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. 
 
All laboratory reports, pathology reports, x-rays, imaging study and scans must have: 
 
Complete identifying information (name and address of the organization performing, 
analyzing, and/or reporting the results of the test); and 
 
Range of normal values for each result listed. 
 
11.4  Data and Safety Monitoring Board 
 
The 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 and ethics. The DSMB report is generated by the statistician and includes a 
summary of accrual, adherence, and retention, descriptive statistics for baseline characteristics 
and patient status, descriptions of all adverse events and toxicities, estimates of data 
completeness, a summary of the primary and secondary outcome measures. 
 
11.5 
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 HIPAA, OHRP, FDA 
regulations and guidance, and NCI/DCP requirements unless the standard at the site is more 
stringent. 
  
Record retention should be 5 years after the study is discontinued for studies without an IND (21 
CFR 312.62). 
 
11.6 
CDUS Reporting 
 

 
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The Wake Forest NCORP Research Base Data Management Center will submit quarterly 
reports to DCP/CTEP by electronic means using the Clinical Data Update System (CDUS). 
 
12. 
STATISTICAL CONSIDERATIONS 
 
12.1 
Study Design/Endpoints 
 
Objectives: The objectives of this pilot study are: 
 
1) To evaluate the feasibility of conducting a randomized phase III study to test the efficacy of 
device-guided breathing in post-treatment lung cancer survivors with significant anxiety.  
Feasibility will be assessed using measures of accrual, participation, adherence, and 
retention.   
2) To collect preliminary data on the variability and efficacy of two doses of a device-guided 
breathing intervention versus a usual breathing control group for reducing anxiety (primary 
outcome) and for improving self-reported cancer-related worry dyspnea, and respiratory 
functioning   (secondary outcomes) in post-treatment lung cancer survivors.  
3) To select the optimal dose of the device-guided breathing intervention (15 minutes once/day 
or twice/day) for a subsequent randomized study. The optimal dose will be defined as the 
one that results in the greatest improvement in anxiety scores at 12 weeks. 
 
A parallel, randomized pilot study will be conducted to address these objectives. Eligible 
patients will be stratified initial dyspnea level and randomized with equal probability to high dose 
device-guided breathing, low-dose device-guided breathing, or a usual breathing control. Study 
endpoints include anxiety (primary outcome: anxiety subscale of the HADS-Anxiety/Depression 
Scale), dyspnea, and respiratory function. These constructs will be measured at baseline and 6 
and 12 weeks post-randomization. Estimates of treatment efficacy will be obtained using the 
“intent to treat” approach. That is, all randomized patients will be included in the primary 
analyses whether or not they were treated according to protocol. 
 
4)  Supplemental Objective: To determine if changes in anxiety attributed to device-guided 
breathing are correlated with epigenetic (DNA methylation) and/or gene expression 
changes. 
 
5) Supplemental Objective: To obtain preliminary data on changes in salivary cortisol (diurnal 
slope, cortisol awakening response, area under the curve) in each intervention group and 
associations between salivary cortisol and anxiety.  
 
12.2 
Sample Size/Accrual Rate 
 
The sample size for this trial will be based on statistical selection theory criterion as described 
by Simon et al.77 For a selection trial, one simply chooses the regimen that results in the “best” 
response. While Simon used this idea in the context of choosing the regimen with the best 
tumor response, the idea is applicable to outcomes with other distributions (in addition to the 
binomial). In our trial, the response is self-reported anxiety, which we will assume is normally 
distributed, so the best regimen will be the one with the lowest mean anxiety score.  We will 
proceed to a phase III trial if one of the RESPeRATE intervention arms results in the least 
anxiety, and the mean anxiety score in that group is at least 0.5 standard deviations (SD) less 
than mean anxiety score in the control group.  The sample size is chosen to ensure a high 
probability of selecting the best arm, assuming that the mean anxiety score in the low dose arm 
is 0.5 SD less than the mean in the control group and the mean anxiety score in the high dose 
arm is 1.0 SD less than the mean in the control arm. Under these assumptions, we used 

 
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simulations to determine the sample size needed in each group to ensure that the probability of 
selecting the best regimen was 90%. We randomly selected n independent observations from 
the normal distribution with an SD = 1, calculated the mean anxiety scores for each group, and 
selected the group with the least observed mean. This was repeated 200,000 times. The 
probability that the best regimen was chosen is calculated as the proportion of times (of the 
200,000 repetitions) that the group with the true lowest mean was selected. In addition to 
selecting the best regimen, we will only pursue a subsequent phase III trial if there is some 
evidence of effect. Thus, we will require that the mean in the best regimen is at least 0.5 SD 
lower than the mean for the control group. Using simulations, we find that 20 patients per group 
provides 90% probability that the best regimen will be chosen and the mean in that group be at 
least 0.5 SD lower than the mean in the control arm. Assuming a 20% dropout, we will accrue a 
total of 75 participants to this study (20x3/.8).  Assuming no effect of the RESPeRATE device, 
we have 90% probability of stopping with the phase II trial. 
  
12.3 
Randomization and Stratification  
 
 
Patients will be stratified by baseline dyspnea (0-7 versus 8+ for CDS total score) and assigned 
with equal probability to either RESPeRATE group or the control group using variable length 
permuted block randomization. Block sizes will be chosen randomly to ensure that future 
assignments cannot easily be inferred from previous ones. There will be no interim analyses for 
this pilot study, and analyses will not be done separately for each stratum. 
 
12.4 
Primary Endpoint(s) 
 
 
 
The primary objective of this study is to collect data that will allow us to assess the feasibility of 
conducting a phase III randomized study of device-guided breathing in lung cancer survivors 
with significant anxiety. These endpoints include: participation, accrual, adherence, and 
retention. 
 
The participation rate will be calculated as the proportion of eligible patients who agree to 
participate.   
 
 
The accrual rate will be calculated as the number of patients accrued to the study divided by the 
number of months of accrual.   
 
The actual amount of time the participant used the device will be retrieved from each device. 
Adherence will be calculated as the actual amount of time the device is used divided by the 
prescribed time.  Successful adherence will be defined as use of the device ≥75% of the time 
assigned. We will also estimate the proportion of patients who use the device more than 
prescribed.  (If “low-dose” participants use the device more than prescribed, this may limit our 
ability to detect a dose effect.) 
 
Retention will be calculated as the number of participants who complete the final assessment 
divided by number randomized. 
 
Confidence intervals for the binomial proportions will be calculated using methods described by 
Wilson.78 Approximate 95% confidence intervals based on the normal distribution will be 
calculated for the continuous measures. 
 
The clinical endpoints are anxiety (primary outcome: anxiety subscale of the HADS-
Anxiety/Depression Scale), cancer-related worry, dyspnea, and pulmonary function at baseline 
and 6 and 12 weeks post-randomization. Estimates of treatment efficacy will be obtained using 
the “intent to treat” approach. Descriptive statistics (means, standard deviations, frequencies, 

 
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etc.) will be presented for each outcome measure at baseline and follow-up points stratified by 
treatment arm. Repeated measures (RM) ANCOVA models (fitted using PROC MIXED in SAS) 
will estimate the treatment effect for each outcome, test for treatment differences, and obtain 
adjusted post-treatment estimates of the variability of these outcomes. Estimates of outcome 
measure variability will be used to determine sample size for the subsequent trial. The primary 
RM ANCOVA model will include time, treatment arm, and the stratification factors.  An 
unstructured covariance matrix will be used to account for the within-patient correlation over 
time. In secondary models, additional covariance structures (Toeplitz, Autoregressive, 
Compound Symmetry) will be assessed and the optimal structure will be chosen based on 
likelihood ratio tests for nested structures and the BIC statistic for non-nested structures. Least 
squares means and 95% confidence intervals will be provided for each outcome, stratified by 
treatment arm, and for the difference between treatment arms. Regression diagnostics and 
residual plots will be used to find appropriate transformations for variables in the model.  
Subsequent RM ANCOVA models will include additional covariates (e.g., age, sex, stage) to 
correct for chance imbalances in important prognostic variables and account for variability in 
outcome measures due to covariates. These latter models will inform us of possible stratification 
factors for the subsequent trial. Limited exploratory analyses will be done to determine if the 
treatment effect differs for different levels of covariates (e.g., by including treatment by covariate 
interactions in the model) to see if the subsequent trial should be done in particular subsets of 
lung cancer survivors. It is likely that some data will be missing. In addition to the mixed models 
above, we will use multiple imputation pattern-mixture models under various assumptions (e.g., 
participants in the active arms who drop out would have subsequent patterns similar to 
participants in the control arm) to assess the sensitivity of our modeling assumptions. 
The optimal dose will be defined as the one that results in the greatest improvement in anxiety 
scores at 12 weeks (based on estimates from the RM ANCOVA model). This dose will be used 
in the subsequent trial, assuming that it is one of the RESPeRATE intervention groups.  
 
Assuming the 95% confidence interval for the treatment effect includes a clinically meaningful 
difference, the sample size for the subsequent phase III trial will be determined based on 
detecting a clinically meaningful difference with a high power using estimates of variability 
obtained in this study. The estimates of retention and adherence observed in this study will be 
used to refine that sample size estimate. Subsequent trial feasibility will be assessed based on 
our ability to recruit the required number of participants. For that, we will use the accrual and 
participation rates observed in the participating sites. For sites that did not participate in this pilot 
study, accrual will be estimated by multiplying the estimated number of eligible patients times 
the participation rate across the participating sites. 
 
12.5 
Secondary Endpoint(s) 
 
Epigenetic and Gene Expression Analyses. 
To characterize the DNA methylation and gene expression patterns between the different 
groups, mixed effects models will be used. Changes of methylation or expression levels will be 
treated as the dependent variables and the intervention groups will be the independent variable 
of interest. Baseline methylation or expression levels, age, chip, chip position, and other 
covariates will be adjusted in the model. After comparing the fit of these data at a set of 20 
random CpG markers (for the methylation analysis only), the alternative paired difference 
between baseline and twelve weeks (percent change dividing the difference by baseline value) 
will be examined to see if it provides a better fit to these data. 
 
To determine if changes in anxiety are associated with methylation or gene expression patterns, 
mixed effects models will be used, and changes in anxiety variables will be treated as the 
dependent variables. Baseline methylation or expression, change of methylation or expression, 

 
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intervention group, and interaction between intervention group and change of methylation or 
expression will be included in the model, along with the appropriate covariates. If the interaction 
effect is significant, it means that the association between the change in anxiety and change in 
methylation or expression proportion is not the same between the two exposure groups. Multiple 
comparisons will be adjusted using Bonferroni correction as before. 
 
Salivary Cortisol Analyses. Participants with endocrine disorders (e.g., diabetes and thyroid 
disorders) or on steroid-based medications are excluded from the cortisol portion of the study 
(topical hydrocortisone cream permitted).  Cortisol levels will be assessed upon awakening, 30 
minutes post-awakening, and at bedtime for three consecutive days at baseline and three 
consecutive days at 12 weeks. Several measures will be derived from the three daily cortisol 
values, including the mean levels at each time, the mean cortisol awakening response (CAR – 
change in cortisol from awakening to 30 minutes), the area under the curve (AUC), and the 
diurnal slope (change in cortisol between awakening and bedtime). Scatterplots and correlations 
will be used to quantitate the associations between these measures, and anxiety at each time 
(baseline and 12 weeks) as well as association between the change in cortisol measures and 
the change in anxiety. Additionally, mixed effects models, as described above, will be used to 
assess the association between baseline cortisol and changes in anxiety over time. To assess 
group differences in cortisol parameters, each of these measures at 12 weeks will be used as 
dependent variables in analysis of covariance models, using appropriate transformations as 
needed. Baseline levels of the measures will be used as covariates along with treatment 
group.   
 
12.6  
Reporting and Exclusions 
 
An objective of this study is to estimate adherence and retention as defined above in Section 
12.4. Note that all participants will be included in all primary analyses, regardless of adherence 
or retention using all data that have been collected.  Secondary analyses will be conducted 
using those participants who were at least 75% adherent to see if the “per protocol analysis” 
gives similar results as the “intent-to-treat analysis.” 
 
12.7 
Evaluation of Toxicity 
 
All participants will be evaluable for serious adverse events from the time of their randomization.  
Toxicities will be evaluated using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.  Fisher exact tests will be used to assess differences in toxicity rates 
between the three arms. 
 
 
 
  
12.8 
Evaluation of Response 
 
 
Tumor response is not an outcome. Response for this study will be the change in anxiety from 
baseline to 12 weeks, and this outcome will be assessed in all participants.  Analysis of this 
outcome is described above in Section 12.4. 
 
12.9 
Interim Analysis 
 
There will be no formal stopping rules based on interim analyses for this pilot study.  However, 
all Research Base studies are reviewed by the DSMB every six months so the data from this 
study will be reviewed on that schedule. The report completed for the DSMB includes a 
summary of accrual, adherence, and retention, descriptive statistics for baseline characteristics 
and patient status, descriptions of all adverse events and toxicities, estimates of data 
completeness, a summary of the primary and secondary outcome measures.    
 

 
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