Study Protocol for the Breathe Easier Trial: A Pilot RCT of a Dyad-Based,Multiple-Behavior Intervention for Improving Physical and Emotional Health in Survivors Facing Lung Cancer

Abstract

Background:

Research targeting survivors of lung cancer has yet to adequately address the management of physical deconditioning and unresolved symptoms (dyspnea, fatigue). The objective of the Breathe Easier trial is to test the feasibility and preliminary effects of a theory-based, multiple-behavior intervention (physical activity, smoking reduction for current smokers, stress management) targeting survivors of localized non-small-cell lung cancer (NSCLC, stages I-III) and their supportive partners.

Methods:

This pilot RCT will enroll 30 dyads (60 participants). Each dyad will consist of one survivor and one partner (defined as a family member or friend) Dyads will be randomized to the Intervention Group (IG) or the Attention Control Group (AC). IG members will receive the 12-week, home-based intervention based on the individual and family self-management theory, which targets improvements in self-efficacy, social support, and self-regulation. Improvement in lifestyle behaviors is a proximal outcome. Improvements in physical and emotional health are distal outcomes. Breathe Easier (IG) includes educational content written in plain language as well as breathing exercises and meditations; SMART goal setting; daily text messaging; and weekly telephone calls with trained staff. The AC program includes relevant National Institutes of Health publications plus weekly telephone chats. Members who currently smoke will also receive an evidence-based smoking cessation resource.

Discussion:

Breathe Easier focuses on changes in multiple behaviors in dyads coping with a diagnosis of NSCLC (stages I-III) with the overall purpose of improving physical and emotional health. Findings will provide additional evidence of the feasibility and preliminary effects of this intervention.

Trial Registration:

ClinicalTrials.gov Identifier: NCT05956782; This trial was registered retrospectively.

Background

Lung cancer is the second-most diagnosed malignancy, accounting for more annual deaths than breast, prostate, and colorectal cancer combined. Approximately 80% of lung cancer diagnoses are non-small-cell lung cancer (NSCLC), and about 42% will present with localized disease (stages I-III). ¹ Greater awareness about early detection and improvements in treatments have led to better outcomes for persons with early-stage diagnoses. ² As early detection continues to improve along with treatments, the 5-year survival rates (currently 57%, stages I-III; 70%, stage I only) are also projected to improve. In short, survivors of lung cancer will be living longer.^1,3

Only a small percentage (5%-10%) of patients with lung cancer are asymptomatic at diagnosis. Cough, dyspnea, wheezing, chest discomfort, bronchorrhea, and fatigue are common symptoms. ⁴ Up to 80% of long-term lung cancer survivors report smoking-related comorbidities such as COPD (Chronic Obstructive Pulmonary Disease), heart disease, and other cancers.^{5 -7} Thoracic surgery, radiation, and chemotherapy may improve or worsen symptoms. After curative surgery, survivors describe persistent physical and psychological symptoms negatively affecting their QOL (quality of life).^{5 -7} The extent of the resection, comorbid conditions, and health behaviors further exacerbate symptoms.^{5 -10} Overall, survivors with lung cancer experience more symptom distress than survivors with other types of cancer.^11,12

Dyadic Approach

Supportive partners (herein referred to as SPs) of survivors of lung cancer must cope with physical and psychological impact on the survivor, themselves, and others.^13,14 SPs not only provide support, but they must also cope with their own concerns, including uncertainty surrounding the survivor’s illness, fear of losing their partner, and the impact of their own health behaviors. SPs report negative emotional effects of being the support person.^{13 -19} Relationships between survivors and SPs are affected by the cancer also.^{17 -19} An emerging consensus in the literature is that when both the survivor and SP are treated simultaneously, the well-being of each individual and of the dyad may improve. When SPs’ needs are not addressed, they are at risk of impaired health.^13,14 Interestingly, most health behavior-related interventions focus on individual behavior. Yet, health behaviors tend to cluster in families and social networks.^{16 -23} The process of interdependence between dyad members plays a role, meaning individuals who interact with each other influence one another’s experience.^19,20 The past decade has seen a growth in interventions exploring the effects of SPs (and their behaviors) on each other when a serious illness is diagnosed in one of them.^19,20 To better understand this influence, a greater emphasis is needed on interventions that target survivors and partners, not only the survivors.

Multiple Lifestyle Behaviors

Cigarette smoking accounts for approximately 85% of the lung cancer burden and up to 90% of the COPD burden.^1,2 Smoking is prevalent among those diagnosed with lung cancer,^{10,21 -25} and most survivors are former smokers at risk for relapse with varying levels of dyspnea. ¹⁰ Multiple unhealthy behaviors often accompany smoking, including insufficient physical activity levels and ineffective stress-management skills. ² Researchers have examined the prevalence of multiple health behaviors in lung cancer survivors, 4 studies targeted dyads.^{21 -24} In one cross-sectional study, data from 37 dyads (mostly white, non-Hispanic) showed high rates of smoking [43%, survivors; 30%, family members (FMs)] and of physical inactivity (84%, each group). In terms of readiness to change, within 6 months post-diagnosis, 63% of patients and 81% of FMs were ready to increase their physical activity, and 88% of patients and 91% of FMs were prepared to stop smoking. ²¹ A qualitative study involving 26 non-Hispanic Black dyads, within 7 years post-diagnosis, revealed fewer current smokers (15%, survivors; 8%, supportive partners [SP]) and persistent physical inactivity (65%, survivors; 42%, SPs). ²² Two more recent studies collected similar data from survivors and their caregivers (mostly white, non-Hispanic) within 1-month post-diagnosis and 6 months post-thoracic surgery; these studies reported that survivors and caregivers were receptive to educational and lifestyle behavior modification programs.^{21 -24}

Compelling evidence exists that continued smoking and physical inactivity adversely affect cancer (including lung cancer) survivors’ prognoses and QOL.^{25 -30} Smoking cessation and physical activity interventions (individually administered) improve QOL and other outcomes. Furthermore, physical activity interventions are well-tolerated, safe, and feasible adjunct therapies that can mitigate several disease- and treatment-related side effects.^{26 -30} A feasibility study with 10 dyads (1 dyad = 1 survivor of early-stage lung cancer + 1 SP ) provided “proof of concept” and showed aerobic training (continuous activity involving large muscle groups), stress management (breathing and meditation practices), and smoking reduction are safe, feasible and acceptable ²⁸ Thus, we are optimistic that this research will advance scientific knowledge about these behaviors being complementary and producing a synergistic effect on behavior change and physical and emotional self-management.

The purpose of the Breathe Easier [BE] trial is to test a multiple-behavior intervention that seeks to achieve stress reduction, increased physical activity, smoking reduction, and abstinence and relapse prevention. We will focus on (1) an understudied population of cancer survivors; (2) diverse survivor/SP dyads as the unit of analysis; and (3) multiple-behavior intervention development and testing. In the short term, this research represents the next step toward understanding the best ways to improve multiple behaviors and therefore reduce the burden of symptoms among survivors of lung cancer and their SPs. The goal of this paper is to describe the rationale and design of the BE trial.

Specific Aims

The long-term goal of this research is to improve physical and mental health outcomes for survivors of localized non-small-cell lung cancer (NSCLC), stages I-III, and FMs (dyads). The primary aim is to determine the effects of a 12-week, theory-guided, evidence-based, multiple-behavior, telephone-delivered intervention to dyads (intervention group, or IG) compared to those in an attention control group (AC) on behavior change. Specifically, the intervention aims to (a) increase exercise capacity and walking steps, (b) increase the use of stress-reducing behaviors, and (c) reduce symptoms (dyspnea, fatigue, stress) post-intervention and at 3 months follow-up. We hypothesize that the IG will demonstrate greater increases in exercise capacity, walking steps, use of stress-reducing behaviors, and symptom reduction relative to those in the AC group.

The secondary aim is to determine the effects of the intervention (compared with those in the AC group) on (a) tobacco use reduction, (b) tobacco use cessation, (c) relapse prevention, and (d) reduction of symptoms (dyspnea, fatigue, stress) for survivors with NSCLC (stages I-III) and their SPs (dyads) who are current smokers at study enrollment. We hypothesize that the IG will demonstrate greater smoking reduction and/or abstinence relative to those in the AC group.

Additional study objectives will explore the associations between affect (ie, affective balance), sleep quality, cognition, cancer-specific treatment sequelae (eg, fatigue, neuropathy), and their associations over time with sedentary behavior (using ecological momentary assessment [EMA]).

Methods

This study is approved by the University of South Carolina Institutional Review Board (Pro00112653). All participants will provide written informed consent.

Theoretical Framework

The individual and family self-management theory (IFSMT) is a descriptive mid-range theory that was developed based on conceptual and theoretical perspectives from systems theory, social learning theory/social cognitive theory, and social support theory, as well as research related to self-management of chronic illnesses. IFSMT proposes that successful change in the self-management of behaviors (physical inactivity, stress management, smoking reduction/abstinence) after a diagnosis of lung cancer requires active involvement by the survivor coupled with family support. ³¹ IFSMT encompasses three broad dimensions: context, process, and outcomes. The context dimension can directly impact individual and family engagement in the self-management process and, therefore, the outcomes. Within the process dimension, self-regulation is the process used to change behavior. Social support enhances the capacity to change and includes influence and collaboration among individuals and dyads. ³² In this study, the intervention impacts the self-management process by promoting self-efficacy, self-regulation, and social support; enhancing these 3 factors, in turn, will lead to improved proximal outcomes (increased stress management, increased physical activity, reduced tobacco smoking, prevention of relapse) and distal outcomes (reduced symptoms of dyspnea, fatigue, and stress).

Design

This study will use a 6-month, longitudinal, 2-group, repeated-measures, attention control pilot randomized control trial (RCT) design.

Settings

Two related clinical sites will be used as recruitment settings. One is an ambulatory cancer center that serves roughly 90% of cancer cases diagnosed in the standardized metropolitan statistical area of Columbia, South Carolina (USA). This center provides comprehensive services, including medical oncology and infusion, radiation oncology, diagnostics and imaging, laboratory, social work case management, nutritional and psychological counseling, retail pharmacy, hospice, and research. The second site in the same region is an acute care setting providing thoracic surgery and nurse navigation services.

Study Sample

A total of 30 dyads will be enrolled. Once a potential participant initiates contact with the team, that person is screened for eligibility (see Table 1). If deemed eligible, the potential participants will be scheduled for the first in-person visit with the research team (see Table 2). There are 6 in-person visits scheduled over 6 months for data collection purposes.

Table 1.

Inclusion and Exclusion Criteria.

Criteria type	Criteria
Inclusion criteria: Survivors	Completed primary treatment for localized NSCLC (stages I-III) Owns or is willing to use a smartphone capable of receiving text messages Willing to complete a 12-week, home-based intervention program that includes in-person and telephone interaction Is willing to consider behavior change at this time Has a partner willing to participate who is at least 21 years old Is able to speak and read English Is capable of informed consent Provides a health clearance form signed by a health-care provider
Inclusion criteria: Support partners	Owns or is willing to use a smartphone capable of receiving text messages Is willing to complete a 12-week, home-based intervention program that includes in-person and telephone interaction Is willing to consider behavior change at this time Able to speak and read English Capable of informed consent Provides a health clearance form signed by a health-care provider
Exclusion criteria: Both	Survivors with a known diagnosis of advanced lung cancer (stage IV), due to potential added burden Anyone for whom physical activity is not recommended as determined by a health provider Anyone with a substantial mobility impairment like rheumatoid arthritis, cerebral palsy, muscular dystrophy, multiple sclerosis, paralysis, Parkinson’s disease, stroke, and/or a history of recurrent falls

Table 2.

Study Timeline.

Time	Study activities
Intervention delivery (12 weeks)
Week 0, day 1	In-person meeting (#1) in clinical or community setting: Informed consent education and signing, baseline data collection, accelerometer orientation and distribution, ecological momentary assessment (EMA) orientation, mobile app downloading and demonstration.
Week 1, day 1	In-person meeting (#2) in clinical or community setting: Accelerometer, accelerometer log collection, and confirmation of quality accelerometer data prior to randomization; randomization to one of two groups; distribution of program materials (manuals and pedometers). Participants added to Mosio texting platform.
Weeks 1-12	Program administration by telephone in the home setting to two groups (IG, AC)
Week 6	Acceptability survey distribution by mail
Week 12	In-person meeting (#3) in clinical or community setting: Repeated measures data collection, accelerometer, accelerometer log, EMA review, collection of 12 weekly logs, distribution of acceptability survey
Week 13	In-person meeting (#4) in clinical or community setting: Accelerometer, accelerometer log collection, confirmation of quality accelerometer data, review taper schedule
Intervention taper (12 weeks)
Weeks 13-24	Program administration by telephone in the home setting to two groups (IG, AC)
Week 22	Acceptability survey distribution by mail
Week 24	In-person meeting (#5) in clinical or community setting: Repeated measures data collection, accelerometer and log distribution, EMA review, schedule exit interview
Week 25	In-person meeting (#6) in clinical or community setting: Accelerometer and log collection, delete EMA mobile app from phones, conduct exit interviews (IG only).

Sample Size

Since pilot studies do not provide meaningful estimates of effect sizes for planning subsequent large RCTs due to the imprecision inherent in data from small samples, our proposed sample size of 30 dyads (N = 60; 15 dyads for each study arm) is based on study timeline, project scope and budget.^33,34

Although analyses will not focus on strict statistical hypothesis testing, but rather estimating effect sizes, we anticipate that given a total sample of N = 30 (15 dyads in each condition), we will have more than adequate power to find effects in the medium size range (f2 = 0.15) for our primary hypotheses assuming small-moderate correlation between dependent pairs (dyads).^33,34

Randomization

The statistician determines the randomization strategy. The group assignments will be generated at an off-site location. A faculty person (someone not associated with this study) will develop a set of sealed, numbered envelopes. Based on a grid developed by the statistician, the randomization assignment will be placed inside each envelope and given to each dyad by the research staff. Dyads who express interest in continuing to participate will be randomized to 1 of 2 groups, each receiving its own intervention protocol: (1) BE Intervention Group (IG) or (2) Survivorship Health Education Attention Control Group (AC). See Supplement for group protocols and detailed intervention content.

Breathe Easier Intervention

Dyads randomized to the intervention group (IG) will receive 4 intervention components. The Breathe Easier (BE) manual written in plain language provides instruction and resources to facilitate learning how to manage stress, increase physical activity and reduce smoking tobacco (if appropriate). Sections of the manual are reviewed with participants during each counseling session. For example, “S.M.A.R.T. Goal Setting” is reviewed first. Other sections include “React to Stress with Greater Ease” (covers identification of internal and external stressors, health impacts of acute and chronic stress, reactions to stress, stress reducers [including breathing exercises and meditations], and improving your sleep) and strategies for participating in and sustaining activity behaviors. Dyads will be encouraged to discuss and set goals, walk, and practice stress management skills together.

A timed, brief telephone counseling session (60 minutes/dyad maximum) with a trained research team member will be scheduled on a weekly basis for the 12-week intervention period. A script and discussion guide will be used. All conversations will be recorded for quality review and fidelity purposes. The primary purpose of the telephone conversation is to provide social support with SMART goal setting, adherence monitoring, and encouragement. After the 12-week period ends, the telephone calls will be tapered to every other week for 4 weeks, then monthly until week 24.

A texting library has been created to provide additional education, support, and encouragement. There are 5 Storylines for the text messages for the BE intervention group: BE Active, BE Kind to Yourself, BE Supportive, BE Smokefree and STAY Smokefree. Text messages will be delivered daily for the first 12 weeks, then tapered. All participants (regardless of group assignment) will receive a weekly text message reminding them of their telephone appointment with the research team member. A company by the name of mosio has developed a platform to deliver the messages on a predetermined schedule. All Storylines and text messages are based in the IFSMT processes of self-efficacy, self-regulation, and social support.

Each participant will be given a pedometer calibrated to their stride (Digiwalkers, Accusplit) to track walking steps. ³⁵ Logs are added to the back of each manual for participants to track their goals and progress with behavior changes. Whether the activities are performed as an individual or with a partner are documented on the logs. These logs are reviewed each week during the Telephone Counseling Sessions.

Survivorship Health Education

Dyads randomized to the AC group will receive survivor and caregiver educational materials. All books are available to the public but not part of usual care in this setting.^36,37 A timed (15 minutes maximum per dyad), brief telephone chat will be scheduled for each dyad with trained research staff on a weekly basis for 12 weeks. A script will be used. All telephone chats will be recorded for quality review and fidelity purposes. The primary purpose of the chat is study retention. After the initial 12-week period, chats will be scheduled every other week for 4 weeks, then monthly until the end of the study. Participants will receive a pedometer customized to their stride, instructions for wear and use, and 12 weekly logs. No further counseling will be offered. Because many survivors of lung cancer struggle with nicotine addiction, smoking cessation and relapse prevention content will be made available. Participants who are current smokers will receive the FOREVER FREE educational program—a free, evidence-based resource consisting of 12 short booklets. ³⁸

Safety and Medical Events Monitoring

A provider clearance form is required for each potential participant. This is an important safety measure because both survivors and SPs may have acute and/or chronic illnesses that impact their study participation. The research team will review the progress of each participant at weekly staff meetings. Study protocol will require that participants in the intervention group be asked, during each weekly telephone call, about any problems that occur during or after walking and counting steps. The research staff will be trained to ask specific questions about changes in medication use and potential side effects, nicotine withdrawal symptoms (if choosing to decrease smoking), chest pain or discomfort, excessive fatigue, muscle soreness, pain (in the back, hips, knees, feet, or joints), and shortness of breath. Responses to these questions will be documented. In the case of a possible serious sign or symptom (eg, chest pain, trouble breathing, changes in heartbeat, fainting, dizziness, or persistent pain of any other kind), participants will be advised to call 911 or activate emergency services in their area. If a participant reports a possible serious sign or symptom, their participation in the study will be placed on “hold” until that participant’s health care provider provides written clearance for resuming the study. If this clearance is not obtained, the participant’s study participation will be terminated. A collaborator who is a physician and pulmonologist will provide guidance on management of any health issues that arise among study participants. This safety protocol has guided similar studies by members of this research team.^{39 -42}

Baseline and Repeated Measures

Baseline measures will be collected once and used to describe the sample. An investigator-designed Participant Information Form will collect demographics and health status data (age, gender, marital status, socioeconomic status, employment status, smoking status, pack-year history, type of SP participating). The Charlson Comorbidity Index will measure comorbidities.^43,44 A Medication Form will be used for participants to list medications at enrollment. Anthropometric measures (weight and height) will be objectively measured in a private room by research staff. Height and weight will be used to calculate body mass index (kg/m²). The information collected using these measures will be confirmed immediately post-intervention and at 24 weeks post-intervention.

Repeated measures are described as context, process, and proximal and distal outcome measures in relation to the theoretical framework. ³¹ All repeated measures will be administered to all participants at 3 time points (baseline, immediately post-intervention [12 weeks], and 24 weeks). After baseline data is collected, all participants will be instructed about the wearing of a wrist accelerometer and responding to Ecological Momentary Assessment (EMA) surveys on their smartphones for a 7-day period prior to randomization.^45,46 Written instructions in plain language about the mobile application, device, and logs will be provided. At the end of the 7-day period, after the accelerometers are returned and completed data is confirmed, the randomization process will take place.

Repeated Measures—Context (Measured at Three Time Points)

• ● Impact of Illness Intrusiveness Scale is a 13-item scale measuring the degree to which their “illness and/or its treatment” interferes with life domains central to quality of life. Responses range from 0 (not very much) to 7 (very much). Not applicable is a choice. Internal consistency is good with a Cronbach’s alpha of .90 for the entire scale. Subscales include Physical Well-Being and Diet; Work and Finances; Marital, Sexual, and Family Relations; Recreation and Social Relations; Other Aspects of Life.^47,48

• ● The Unidimensional Relationship Closeness Scale is a 12-item scale measuring closeness of social and personal relationships. Closeness is conceptualized as the degree of interdependence occurring between relationship partners. Reliability and validity were assessed with a variety of attachments, including friends, couples, and family members. Regardless of the relationship type, the more interdependent the people, the closer the relationship. Each item is accompanied by a 7-point Likert scale. Items are averaged to create a single closeness score. The greater the score, the greater the closeness. Responses range from 0 to 4 and the score is totaled for the 2 subscales. ⁴⁹

• ● Smoking status is measured subjectively and objectively. Current smoking status is not required for participation. Participants will self-report abstinence since quit date (yes/no) and number of days without smoking in previous 7 days (0 -7).^50,51 Verification of self-reported smoking status will be performed by an immune-chromatographic assay that quantifies cotinine (a major metabolite of nicotine with a relatively long half-life [10-40 hours.]) will measure tobacco abstinence. Participants will be given a kit that includes a plastic funnel and asked to drool saliva into it. About 3 ml of saliva is needed. The saliva sample will be frozen in a laboratory freezer (−80°C) and mailed in batches on dry ice to Salimetrics LLC for analysis. Other than the study identification number, no identifying information will accompany the saliva sample. The sample collection will be conducted by research staff. Results will be reported as a continuous variable. Optimal cut points differ by race/ethnicity and gender. Each person’s results will be reported as __ng/ml (and interpreted using guidelines at https://salimetrics.com/guidelines-for-interpreting-cotinine-levels-united-states).

• ● Nicotine dependence will be measured by the Fagerström Test for Nicotine Dependence, a 6-item test. Scores indicate the level of dependence: low (1-2), low to moderate (3-4), moderate (5-7), or high (8+). ⁵²

Repeated Measures—Process (Measured at Three Time Points)

• ● Self-Efficacy for Exercise Questionnaire is a 9-item generic measure assessing whether participants can exercise in a variety of circumstances (eg, “when I am tired”). Each question uses a 5-point scale (1 = not at all confident, 5 = extremely confident). The responses are summed; higher scores indicate greater confidence. Test reliability is .90. ⁵³

• ● Smoking Self-Efficacy/Temptations Scale has 3 scales: (1) Positive Affect/Social Situations, (2) Negative Affect Situations, and (3) Habitual/Craving Situations. Responses range from 1 (not at all tempted) to 5 (extremely tempted). Summing the responses provides an overall score ranging 20 to 100; lower scores indicate greater self-efficacy. Reported reliability coefficients range from .88 to .92. ⁵⁴

• ● Social Support for Exercise Scale has 13 items (rated 1-8) on 2 subscales (family and friends) for a total of 26 questions. The higher the score, the greater the social support. ⁵⁵

• ● Physical Activity Enjoyment Scale (PACES) is an 18-item measure that assesses how participants feel at the moment about the physical activity that they have been performing. Participants are instructed, “Please rate how you feel at this moment about the physical activity you have been doing,” with scales ranging from 1 to 7; the scale for one sample item is “1 = I enjoy it; 7 = I hate it.” Total scores range 18 to 126. The higher the score, the greater the enjoyment. ⁵⁶

• ● Partner Interaction Questionnaire is a 20-item questionnaire assessing a spouse or living partner’s support for quitting tobacco use. The questionnaire includes 10 positive and 10 negative behaviors that a partner might exhibit. Responses for each item on a 5-point scale are as follows: never (0), almost never (l), sometimes (2), fairly often (3), and very often (4). Separate scores are calculated for positive and negative behaviors by summing responses to the 10 items within each subscale. Internal reliability (Cronbach alpha) was .89 for the positive scale and .82 for the negative scale. ⁵⁷

• ● Processes of Change is a 40-item scale measured on a 5-point rating system. There are 10 subscales (related to tobacco use): Consciousness Raising, Self-Liberation, Dramatic Relief, Counterconditioning, Stimulus Con-trol, Helping Relationships, Environmental Re-evaluation, Social Liberation, Self-Reevaluation, and Reinforcement Management. ⁵⁸

Repeated Measures—Proximal Outcomes

• ● Self-reported physical activity will be assessed daily using data collected from a pedometer by participants, who will record their step counts in their weekly logs (part of their self-management plan/self-regulation process). ³⁵

• ● Exercise capacity will be measured at 3 time points with the 6-Minute Walk Test (6MWT). The test measures exercise tolerance on an interval scale. Participants walk on a level path at their own pace, covering as much ground as possible in 6 minutes. Standard phrases will be used to encourage maximal effort; however, slowing down or stopping and restarting will be permitted. The score is the distance traveled in 6 minutes. ⁵⁹

Actigraph is a 3-axis accelerometer (ActiGraph LLC, Pensacola, FL; Bluetooth Smart wGT3X-BT; https://www.actigraphcorp.com) featuring digital filtering technology, with ambient light sensors. The FDA-approved, wireless, noninvasive monitor resembles a wristwatch (and is worn with a Velcro wrist band). It provides 24-hour physical activity and sleep measurements, including energy expenditure, steps taken, physical activity intensity (sedentary, light, moderate, vigorous, and very vigorous), and participant position. The device has a touch sensor to determine whether it is on or off, allowing a “wear time” measurement. The ActiGraph will be worn by each participant for 24 hours over a 7-day period at 3 time points. A wear time of at least 70% over 7 days is required. The collected information will be stored in the device with an identification number (and no other identifying information) associated with each participant. The data will be downloaded with licensed software purchased from ActiGraph on a computer at the University of South Carolina College of Nursing. Data on sleep-wake parameters will be obtained by the ActiLife software developed to process the ActiGraph data. ⁴⁵

Repeated Measures—Distal Outcomes (Measured at Three Time Points)

• ● Dyspnea will be measured using 3 instruments. The Functional Assessment of Chronic Illness Therapy (FACIT)-Dyspnea Short Form (Parts 1 and 2) includes 10 items (Part 1) with 10 other items (Part 2) focused on functional limitations. The short form is rated on a 4-point rating scale over the past 7 days: 0 (not short of breath [SOB]), 1 (mildly SOB), 2 (moderately SOB), and 3 (severely SOB). The higher the score, the worse the dyspnea. Functional limitations are rated on a similar 4-point scale. Total scores range 0 to 40 on both measures. Alpha coefficients: .922 and .928, respectively. ⁶⁰ Dyspnea mRC is a 1-item scale that comprises 5 statements describing almost the entire range of respiratory disability, from none (Grade 1) to almost complete incapacity (Grade 5). This measure can be self-administered by asking subjects to choose a phrase that best describes their condition, for example, “I only get breathless with strenuous exertion” (Grade 1) or “I am too breathless to leave the house” (Grade 5). ⁶¹

• ● Fatigue will be measured using the Functional Assessment of Chronic Illness Therapy Scale (FACIT)-Fatigue (V.4). This 13-item scale is a brief, reliable, and valid measure of the physical and functional effects of fatigue. The level of fatigue is measured on a four-point Likert scale (4 = not at all fatigued to 0 = very much fatigued). The range of scores is 6 (high fatigue) to 52 (low fatigue).^62,63

• ● Hospital Anxiety and Depression Scale (HADS) is a 14-item scale, with half of the items measuring anxiety, the other half depression. Each item is measured on a scale of 0-3 (3 = higher symptom frequencies). Scores for each subscale (anxiety and depression) range 0-21, categorized as follows: 0-7 = normal, 8-10 = mild, 11-14 = moderate, 15-21 = severe. ⁶⁴

• ● Perceived Stress Scale is a 10-item scale scored by reversing the scores on 7 positive items and summating across all 10 items. Items are general in nature. Measures perceived stress over the past 30 days. Five response options: 0 = never, 1 = almost never, 2 = sometimes, 4 = often, 5 = very often. Total scores range 0-21: 21 = very high perceived stress; 16-20 = high; 12-13 = average; 8-11 = low concern; 0-7 = very low concern. ⁶⁵

• ● SF-36v2 Health Survey is a 12-item scale measuring quality of life. It is a reliable and valid measure of physical and mental health. It assesses 1 or 2 questions per domain: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Each health domain score contributes to the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. ⁶⁶

Exit Interviews

Dyadic exit interviews will be conducted with all dyads in the IG group at the end of study participation (in week 24). Interview questions and probes will explore relationship quality and self-management processes. The interviews will be conducted using an interview guide and should take about 1 hour to be recorded. ⁶⁷ Audio recordings will be transcribed professionally and analyzed using content analysis.

Ecological Momentary Assessments (EMAs; Measured at Three Time Points)

EMAs is described as an emerging method to assess an individual’s current thoughts, affect, behavior, physical states, and contextual factors as they occur in real-time and in their natural environment. In a scoping review, EMAs among persons with cancer were found useful and feasible for cancer research assessments. ⁴⁶ In this study, the EMA application is provided by a platform called ExpiWell (https://www.expiwell.com/). It is a valid EMA platform used to measure physical and mental health in populations with chronic illnesses. This software provides encrypted data storage, easily customized features, and cloud storage to allow participants to download each assessment at home. At baseline, the participants will download the ExpiWell app onto their smartphones and access their account by typing in a personal access code (provided by ExpiWell). No names or personal information is associated with the EMA app or web platform. Once the app is downloaded and accessed using the personal code, the participant will be guided by the research team member to complete practice prompts. Participants will complete the practice prompts in the first face-to-face visit with the staff to make sure they understand the items and can respond properly. The practice prompts reflect the same type of questions as the anticipated surveys.

• Morning prompt: Participants will be prompted to respond to 22 sleep-related questions, mostly from the Pittsburgh Sleep Quality Index. In addition, participants will be prompted to respond to 7 statements from the PROMIS Dyspnea Emotional Response Item Bank (once daily).^68,69

• Daytime prompts: Participants will be prompted to respond to 10 mood-related questions from the PANAS Short Form. In addition, there are 5 general questions (3 times daily). ⁷⁰

• Evening prompt: Participants will be prompted to respond to 2 general questions about their typical day followed by 3 statements assessing lower extremity neuropathy (taken from the FACT/GOG-NTX-13 [Version 4], partial). In addition, 9 questions from the Sedentary Behavior Questionnaire (SBQ), 4 questions from the PROMIS Cognitive Assessment, and 12 questions from the PROMIS-Ca Bank v1.0-Fatigue will be prompted (once daily).^{71 -74}

Following each 7-day (accelerometer and EMA) assessment at 3 time points (baseline, post-intervention [12 weeks], 24 weeks), participants will return the accelerometer. At that time, quality accelerometer data and satisfactory completion of the EMA assessments will be confirmed.^45,46 For EMA, completion of at least one survey (morning, daytime, and evening) daily is required.

Recruitment

Survivors will be recruited from a medical and radiation private oncology practice and an American College of Surgeons (ACOS)-approved Integrated Network Cancer Program at a community hospital in central South Carolina. For the purposes of this study, a SP” will be defined as a relative or a close friend. A participating SP is required for survivor enrollment. Several strategies will be used to maximize recruitment, retention and to build trust among the survivor, SP, and research team.

As a primary recruitment method, a partial HIPAA (Health Insurance Portability & Accountability Act) waiver of authorization will be requested from the Institutional Review Board (IRB) so the research team can mail an invitation—a one-page, culturally sensitive, colorful flyer that includes a study telephone number and email address (to RSVP or get more information about the study)—to all potential participants identified through a cancer registry database. This IRB-approved invitation will be sent up to 3 times to approximately 500 survivors of lung cancer (stages I-III). Within a week of the first anticipated invitation’s arrival, telephone contact will be initiated by the research staff. Using a script, research staff will screen survivors indicating interest in participating to determine eligibility. Additional follow-up contact will be made after the survivor has had adequate time to decide and speak with an SP about participating. These phone interactions are designed to strengthen trust, build credibility, and increase understanding and adherence to the study protocol.

A secondary recruitment method will involve the assistance of clinical partners (pulmonology and medical oncology office staff and nurse navigators) who have pre-established relationships with the potential participants. The staff of these offices will recruit potential participants in person as they encounter them in their daily practice during the recruitment period.

Anticipated Challenges With Recruitment

Recruitment of dyads is an anticipated challenge. Although SPs are a primary source of support for survivors with cancer, they are rarely included in research studies.^75-77 Yet, important health decisions are seldom made by survivors alone, and, as in the case of health behavior change, one person’s decision will affect the health of the other(s). When SPs are included in the research process, study procedures become more complex. In dyad-targeted research, barriers to recruitment and retention are multiplied as participation becomes dependent on more than one person’s willingness and ability to participate.^75-77

Lessons learned from preliminary studies will be incorporated into this proposed research.^16,40,42 In one study, a 44% recruitment rate and a 100% retention rate were realized over 6 months. The short recruitment period (6 months), plus the requirement that both dyad members be current smokers living in the same household, negatively affected recruitment. ⁴¹ The Covid-19 pandemic dramatically slowed recruitment for the feasibility study. Survivors were unwilling/afraid to leave their homes, and the Cancer Center was not open to any nonessential services. ⁷⁷ We expect that some hesitation may still exist due to Covid-19 concerns.

Analysis Plan

As a preliminary step, baseline demographic characteristics and medical histories will be compared between groups (IG and AC), for survivors and SPs separately, as well as aggregated across the dyads, using t-tests (for continuous variables) and chi-squared tests (for categorical variables). We will additionally consider whether within-dyad correlations in baseline measures differ across dyads—for example, whether the association between baseline sleep and physical activity within-dyad differs across pairs. Sleep data will be reviewed and analyzed across the 3 time periods. A dyadic analysis will be used as follows: using a series of longitudinal mixed effects models,^{78 -81} the effect of intervention versus control on changes in symptoms (shortness of breath and fatigue) after baseline will be estimated. Specifically, mean symptom score at follow-up (end of 12-week intervention, and 3-month follow-up) will be simultaneously regressed on group, time, group x time, baseline value, and covariates not balanced by randomization. In addition, models will control smoking status. Interactions between smoking status at study entry within the intervention group will be explored, as it is hypothesized that the effect of the intervention will be greatest among those who were smoking at study entry.

Models will include a subject-specific intercept to adjust for repeated measures of the outcome within participants. Models will be run for the study pool (survivors and SPs, considered as dyadic units) with clustering by dyad. This will adjust standard errors for the dependence of outcomes within the dyad by including an interaction term between participant (survivor vs. SP) and treatment group (intervention vs. control). ⁷⁸

As this is a pilot study, the interest is in estimating effect sizes and corresponding 95% confidence intervals, rather than strict statistical hypothesis testing.^33,34 Similar analyses will be run to estimate intervention effects on physical activity (exercise capacity, minutes of light/moderate-intensity activity both objectively measured and self-reported, and sedentary time) and to explore intervention effects on changes in exploratory variables (context and process measures) over time. Finally, using a series of longitudinal regression models implemented with generalized estimating equations with robust standard errors and clustering by dyad, the effect on smoking outcomes at follow-up (abstinence) will be estimated.^79,81 Specifically, binary indicators of abstinence on treatment assigned (intervention vs. control) and potential covariates (including variables not balanced by randomization) will be regressed using binomial errors, a logit link function, and a working unstructured correlation to accommodate within-subject correlation. Coefficients will be standardized, and models will be run with the subsample of dyads where at least one member smoked at study entry. All models will be run with the intent to treat the sample with all randomized participants included. We will also explore changes over time in secondary measured variables (eg, process measures, sleep) and potential moderators of the intervention effect, using a similar analytic strategy to that described above. Moderator analyses will be explored by including the main effects of the potential moderators (in the model of physical activity behavior, for example), as well as interaction with the treatment group.

Data and Safety Monitoring Committee

A Data Safety Monitoring Board has been established to ensure safety oversight. The board will meet twice a year with ad-hoc review and additional meetings called when necessary. The 3-person board includes a senior researcher and 2 assistant professors—one of whom is a nurse who specializes in clinical research with individuals with cancer. Any protocol modifications will be submitted and reviewed by the Institutional Research Board as documented in the clinical trial registry.

Discussion

The BE randomized control trial is testing an innovative, 6-month, theory-based, telephone-delivered approach to promoting changes in multiple behaviors to improve physical and emotional health in survivors of lung cancer and their SPs (dyads). In this study, we compare an AC group that receives general survivorship health education and a pedometer with an IG that receives specific theory- and evidence-based behavioral content delivered in 3 formats (printed materials written in plain language, text messaging, and telephone interaction). We hypothesize that participants in the IG will exhibit greater behavior change (physical activity, stress management, smoking reduction) and symptom self-management (dyspnea, fatigue, stress) than those in the AC.

To date, there are no multiple-behavior interventions designed specifically for dyads that include survivors of early-stage lung cancer and their family members. BE targets a vulnerable and underserved subgroup of survivors who have serious other chronic conditions, generally desire recovery programing, and tend to prefer home-based programing that is safety oriented. Novel features of this study will include provision of information about the promotion of self-management processes (self-efficacy, self-regulation, social support) to facilitate recovery from the treatment for early-stage lung cancer.

Sample size and recruitment from within one state (South Carolina) are potential limitations to this trial. These 2 issues limit the generalizability of our results. Both groups are receiving pedometers and weekly logs for tracking behavioral activities. This lack of a true control group may limit our ability to isolate the effects of the intervention. Thus, any effects of the BE study will need to be considered with caution.

Supplemental Material

sj-docx-1-ict-10.1177_15347354231212876 – Supplemental material for Study Protocol for the Breathe Easier Trial: A Pilot RCT of a Dyad-Based, Multiple-Behavior Intervention for Improving Physical and Emotional Health in Survivors Facing Lung Cancer

Supplemental material, sj-docx-1-ict-10.1177_15347354231212876 for Study Protocol for the Breathe Easier Trial: A Pilot RCT of a Dyad-Based, Multiple-Behavior Intervention for Improving Physical and Emotional Health in Survivors Facing Lung Cancer by Karen Kane McDonnell, Jeannette O. Andrews, Chih-Hsiang Yang, Brandi R. Newsome, Ella Weinkle, Jean Elizabeth Davis and Shira Dunsiger in Integrative Cancer Therapies