Reducing Sleep disTurbance in Cancer

Study Overview
=================
Brief Summary
-----------------
In a randomized controlled trial (RCT), the investigators will recruit participants to an 8-week app-based wellness intervention: the active daily meditation intervention (Calm) or the health education podcast control group (POD), followed by a 12-week follow-up period. The investigators will recruit a total of 276 self-declared Chronic Hematological Cancer (CHC) patients who (representative of age, race/ethnicity, and gender) will be on stable CHC pharmacologic therapy (if any), self-identify as sleep disturbed (>5 on Pittsburgh Sleep Quality Index), do not have a sleep disorder diagnosis, do not take sleep medication/supplements >3 times per week, and are not currently practicing regular meditation. Aim 1: Test the efficacy of daily meditation (10 minutes/day) delivered via Calm compared to POD on the primary outcome of self reported sleep disturbance (Insomnia Severity Index (primary) and PROMIS Sleep Disturbance (secondary)) and secondary sleep outcomes including sleep impairment (PROMIS Sleep Impairment Scale) and sleep efficiency measured via sleep diaries and actigraphy. Hypothesis: Participants who are administered Calm will experience reduced sleep disturbance, and improvements in secondary sleep outcomes compared to POD at eight weeks. Aim 2: Test the efficacy of daily meditation (10 minutes/day) delivered via Calm compared to POD on inflammatory markers (i.e., TNF-a, IL-6, IL-8, CRP), fatigue, and emotional distress (i.e., anxiety, depressive symptoms measured with PROMIS®). Hypothesis: Participants who are administered Calm will have greater reductions in fatigue, emotional distress and inflammatory markers compared to POD at eight weeks. Aim 3: Explore the sustained effects (i.e., 20 weeks from baseline) of Calm in CHC patients. Hypothesis: (a) Participants in Calm will have greater reductions in sleep disturbance, fatigue, emotional distress and inflammatory markers compared to POD at 20 weeks; (b) Total meditation time and sustained meditation usage overtime, but not time of day or use of non-meditative content (e.g., Sleep Stories), will be related to improved outcomes at 20 weeks.

Detailed Description
-----------------
Background: Hematological cancers account for 11% of all cancer diagnoses in the US. Chronic hematological cancer (CHC) patients are characterized by long term and high symptom burden. Up to 65% of CHC patients report chronic sleep disturbances (e.g., difficulty falling asleep, difficulty staying asleep, nonrestorative sleep, insomnia) that are highly correlated with poorer cognitive and physical functioning, increases in fatigue and emotional distress, and heightened levels of specific inflammatory markers (TNF-a, IL-6, IL-8, CRP) that negatively impact quality of life. Sleep interventions have been tested in solid tumor patients, but no research has examined sleep interventions specifically for CHC patients. Medications are commonly prescribed but often come with side effects and risk for long-term dependence. Cognitive behavioral therapy for insomnia (CBT-I) is the most studied and first line of therapy for treating sleep disturbances in cancer patients, but CBT-I is time-consuming, resource-intensive, and not easily accessible for all cancer patients. There is a need for long-term, accessible, non-pharmacologic interventions targeting sleep in CHC patients. RCTs have shown meditation and mindfulness-based interventions lead to improvements in sleep disturbance among breast cancer patients, but this research has not been extended to CHCs. Meditation has potential as a non-pharmacologic strategy to reduce sleep disturbance in CHC patients without the time and expertise limitations of CBT-I and side effect risks from medication. In person meditation, however, is still inaccessible long term due to potential fatigue, pain, transportation, and scheduling difficulties. Smartphone apps have attracted considerable interest from cancer patients as an easily accessible and empowering way to self-manage health. Existing research using apps has focused on short term psychological measures (e.g., distress, cancer-related distress, anxiety, etc.) or cancer-specific biological changes as outcomes and not sleep disturbance, in solid tumor survivors with minimal residual disease (e.g., breast cancer post-treatment), or those with short survival (e.g., metastatic solid tumor patients). The unique, long-lasting disease course of CHC patients and high chronic symptom burden warrants distinct interventions from resolved solid tumor patients. CHC patients with sleep disturbance have no options for easily accessible and evidence-based treatments for sleep disturbances. The investigators propose the first RCT to determine the effects of a consumer-based mobile meditation app on sleep disturbance in CHC patients. The investigators have a unique academic-industry partnership with the consumer-based meditation mobile app, Calm. Calm has the broad reach and popularity to deliver meditation to remote CHC patients. The investigators' formative work shows Calm to be a feasible and preferred method for delivering meditation to CHC patients (including older adults) compared to another meditation app. Notably, patients reported significant post-intervention reductions in sleep disturbance in only four weeks. The health education podcast, with no significant effects on sleep, matched for attention, time, and dose is shown to be an acceptable and appropriate active control to compare to Calm. Study Timeline: This study is expected to last 5 years. The investigators will begin recruiting in January 2023 and expect, based on enrollment rates of prior feasibility and pilot work, an average monthly enrollment rate of  10 participants each month. The investigators will recruit 276 CHC patients and enroll them into the intervention between months 9-48 ( 39 months; providing a small buffer of time to finish recruitment and enrollment if needed). The investigators expect to enroll the last study participant in month 48, meaning intervention delivery will be completed by month 50 (i.e., 8-weeks after last participant is enrolled) and follow-up will be completed by month 53 (i.e., 20-weeks after last participant is enrolled). The investigators are confident the investigators can enroll participants in less than 39 months because in two prior studies recruiting hematological cancer patients for online yoga, 244 and 260 completed eligibility within a month (2015 and 2016, respectively). In the investigators' feasibility study for meditation apps the investigators recruited 289 for eligibility in two months and enrolled 128 CHC patients in four months. Monthly, the investigators will conduct team meetings and check on data quality and conduct data safety monitoring board reviews once each year. Upon the completion of data collection in year 5 (i.e., month 53), the investigators will perform data analysis and write manuscripts for publication. Objectives: Objective #1: Test the efficacy of daily meditation (10 minutes/day) delivered via Calm compared to POD on the primary outcome of self-reported sleep disturbance (Insomnia Severity Index (primary) and PROMIS Sleep Disturbance (secondary) and additional secondary sleep outcomes including sleep impairment (PROMIS Sleep Impairment Scale) and sleep efficiency measured via sleep diaries and actigraphy. Objective #2: Test the efficacy of daily meditation (10 minutes/day) delivered via Calm compared to POD on inflammatory markers (i.e., TNF-a, IL-6, IL-8, CRP), fatigue, and emotional distress (i.e., anxiety, depressive symptoms measured with PROMIS®). Objective #3: Explore the sustained effects (i.e., 20 weeks from baseline) of Calm compared to POD in CHC patients. Recruitment: Given the prevalence of sleep disturbance and based on prior success and experience in recruiting of other rare hematologic malignancy patients, the investigators are confident that they can recruit 10 participants per month. The investigators will recruit 276 CHC patients nationally using successful recruitment strategies used in prior work. These strategies include: postings on both hematological-specific and general cancer social media pages (i.e., Facebook, Instagram, and Twitter), postings on hematological-specific and general cancer email listservs, contact with organizational partners (e.g., Leukemia & Lymphoma Society, MPN Research Foundation, Patient Empowerment Network) to post recruitment information on their website and social media/support group sites, and direct contact with hematological cancer patients who previously expressed interest in future studies. Recruitment materials will include a brief study description, eligibility requirements, study team contact information, and a direct link to the RedCap eligibility survey. Recruitment flyers and postings will be tailored for email listservs and different media platforms (Instagram stories, Facebook and Twitter posts, etc.) with organizational partners (e.g., Leukemia & Lymphoma Society, MPN Research Foundation, Patient Empowerment Network). Copyright images included in recruitment will feature diverse individuals (older adults, male and female, and racial/ethnic minorities). For example, because 45% of hematological cancer patients are women, the investigators will have Facebook posts that target women and men differently. Participants will be told prior to randomization to their group that they will be randomized to an app-based wellness study for hematological cancer patients and thus will be blinded to the intended arm assignment. In addition to using established recruitment methods from past studies, for this study the investigators will utilize existing resources at the Mays Cancer Center at UT Health San Antonio MD Anderson. In particular, the investigators will work with UT Health San Antonio MD Anderson Marketing and Communications Specialists and Media Department to develop and strategically deliver a targeted, nationwide recruitment campaign with a focus on men, racial/ethnic minorities and older adults. The investigators will work in consultation with the Marketing and Communications Specialists and Media Department to develop social media marketing content specifically tailored for men and older adults. In addition, the investigators will spend considerable efforts using Facebook accounts/pages/groups associated with Mays Cancer Center to purposefully recruit a more diverse cancer patient population sample. These recruitment strategies have also been used in prior studies to successfully recruit diverse samples of cancer patients. Enrollment: All study procedures are remote. Interested patients will complete an online eligibility survey via RedCap. Ineligible participants will be sent an email notifying them of their ineligibility status. Eligible participants will be sent an email notifying them of their eligibility, asked to review a video-based overview of the study (including the informed consent), and an invitation to electronically sign the informed consent via RedCap. Once the consent is signed, participants will be asked to complete the baseline survey via RedCap. After the informed consent and baseline survey has been completed, participants will receive a study Welcome Email that contains baseline blood draw instructions and Oura Ring sizing instructions. Participants will be asked to wear an Oura Ring throughout the entire 20-week study period (starting at baseline) and to go to a LabCorp lab near to their home for the baseline blood draw. Instructions for the Oura Ring and the baseline blood draw will be emailed to the participant and the Oura Ring will be mailed to their home address they provide within the Baseline Survey. Participants will be instructed to reach out to the study team via email or phone with any questions. The blood draw instructions will contain a step-by-step process for study participants to setup a blood draw appointment at the closest LabCorp lab to them. LabCorp is a large CAP/CLIA accredited laboratory system with centers located across the U.S. Authorized accounts will be set up for each participant. The investigators will ask participants to have their blood drawn within two weeks of completing the baseline survey, and to repeat their blood draw at post-intervention (eight weeks), and follow up (20 weeks). Participants will not have to be fasting in order to receive their blood draw. The research team will access the blood draw data using the LabCorp system's web-based patient platform that provides a secure and confidential location to store and view test results (i.e., information is only accessible with an authorized account). The research team will check the status of blood draw data for study participants weekly in order to ensure compliance. The Oura Ring packages will be mailed individually to each participant directly from the Oura Ring company headquarters. Initially, a research team member will go to an Oura Ring portal and have an Oura Ring sizing kit sent to each study participant as they are enrolled (after completing Informed Consent and Baseline Survey) at the mailing address they provided in their Baseline Survey. This kit should arrive to the participant's home within 3-5 business days. Participants will be instructed to find their correct ring size using the sizing kit, email the research team with their ring size. A research team member will then ship the correct size Oura Ring device to the study participant from a bulk supply of rings that will be stored at the Mays Cancer Center in a secure location. At this time, participants will receive an Oura Ring shipment confirmation email along with device setup instructions attached to the email. The Oura Ring package should arrive to the participant's house within 3-5 business days and participants are instructed to email the research team as soon as they receive their device in the mail. Participants will wear the Oura Ring throughout the entire study project period, including through follow-up (i.e., week 0 through to week 20). At the end of the study, participants will be asked to send the Oura Ring device back to the Mays Cancer Center in the pre-paid mailing envelope that will be sent to them initially when they receive their Oura Ring at the beginning of the study. Participants will also be asked to complete a brief, daily sleep diary as well throughout the entire project period. The sleep diary will take around five minutes to complete and participants will complete the sleep diary online. A link will be texted or emailed to them every morning (based on their specified communication preferences) containing the sleep diary. One day per week, the message with the sleep diary will also include a reminder to use the assigned app (Calm for participants and POD for control). After the baseline blood draw has been completed and the Oura Ring package received, participants will be randomized to one of two groups: 1) at least 10 minutes per day of Calm meditation (Calm group) or 2) at least 10 minutes per day of health education podcasts (POD control group), both delivered via a smartphone app. Specifically, participants will be blocked or stratified by gender and then randomly allocated (with a 1:1 allocation) within the male-female strata to treatments using a pseudorandom number algorithm provided by the study statistician (Co-I Dr. Michael Todd). Research personnel who assign participants to a group will not be the same as those who enroll participants or download and clean data. Additionally, group allocation status will be restricted so that research personnel downloading data will remain blind to treatment assignment. After randomization, study participants will receive a Study Start Email that contains their group assignment instructions and will be offered an app familiarization call with a study team member (either a study coordinator or postdoctoral fellow) to review the Calm or POD app, depending on their assigned group. For the current study, during the app download app familiarization call with participants a study team member will review 1) the general layout and basic functionalities of the app (e.g., look, feel, types of content found on app, etc.), 2) where to find content and how the content is organized (i.e., meditations or podcasts), 3) how to view participation tracking stats on the app, 4) how to set reminders to meditate/view podcasts, and 5) how to share participation stats on social media. After all the above has been completed, study participants will have completed their baseline measures and will be ready to participate in their assigned group for eight weeks. Intervention Procedures: Intervention Group Calm meditation focuses on mindfulness components, breathing techniques and body scans, all of which are consistent with core mindfulness practices, including Mindfulness-based Stress Reduction (nonjudgmental moment-to moment awareness) and Vipassana (objective observation of physical sensation in the body). Calm does not provide its users with a specific prescription nor durations or frequencies in which to engage with the app, instead the frequency, dose, and timing of engagement, as well as its content and use of features is entirely self-selected by the user. Participants assigned to the Calm group will be asked to complete a minimum of 10 minutes per day of meditation, at any time of day they choose for eight weeks. During weeks 1-4 participants in the Calm group will be asked to complete the introductory 30-day program How to Meditate (i.e., 30 days of a 10-minute daily meditation with education about what mindfulness is, how to practice it and achieve it with meditation, which seated or laying positions to use for meditation, and how to monitor their breathing). How to Meditate educates participants about how mindfulness meditation affects daily life, such as reducing stress and quieting the mind. Weeks 5-8, participants will be asked to complete one daily meditation that may include the Daily Calm, a different 10-minute mindfulness meditation each day, or a meditation from a various series of meditations (e.g., loving-kindness, seven days of managing stress). Participants will have complete autonomy to choose the meditation. After the participant has completed their daily meditation, participants will also be able to use the app content more broadly (i.e., non-meditative content including Sleep Stories) based on their preference. Participation (meditations completed, time of day, length of time, non-meditative content used) will be tracked using the Calm app throughout the study and addressed in sensitivity analyses. Calm provides secure access to release-consented patient data. Control Group Similar to the Calm group, participants in the POD group will listen to a minimum of 10 minutes per day of a health education podcast delivered via a mobile app for eight weeks. Content was carefully chosen to exclude any recommendations for sleep, meditation, or for mindfulness-like principles or practice. A library of podcasts is available on the app. Participants are able to select the podcast based on title, time or both in an effort to mirror the delivery of the meditations in the Calm group. Similar to the Calm group, the POD group will be encouraged to use the other components of the podcast app (which will be reviewed in detail during the app familiarization calls). Participation (podcasts completed, time of day, length of time, components used) will also be tracked on the app throughout the study period. The app used in the POD group was developed by Alex Fajkowski, founder of Apparent Logic and a software design developer (will also serve as consultant). The app was developed so that functionality and features of the app mirror those of the Calm app that will be utilized by the POD participants in the study. Follow-Up After the intervention (eight weeks), the research team will notify participants that they will no longer receive email/text reminders but will still have free access to their app for three months. The investigators will continue to track participation of Calm/POD until 20 weeks from baseline.

Official Title
-----------------
Consumer-Based Meditation App, Calm, for Treatment of Sleep Disturbance in Hematological Cancer Patients

Conditions
-----------------
Cancer, Sleep Disturbance, Anxiety, Depression, Inflammation, Fatigue

Intervention / Treatment
-----------------
* Behavioral: Calm Meditation
* Behavioral: Health Education Podcast


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Self-declared diagnosis of hematological cancer on stable maintenance management* by treating physician (i.e., on stable medical therapy) or observation (i.e., no changes in disease targeted medications for the past two weeks) Not currently participating in a therapeutic pharmacologic clinical trial Not planning to receive an allogenic stem cell transplantation during the study time frame (i.e., 20 weeks) Score of >5 on PSQI (Pittsburgh Sleep Quality Index) Own a mobile smartphone (iPhone with iOS 14 or later or an Android 6 or later) with an active data or WiFi connection Willing to download two mobile apps Able to read/understand English ≥18 years of age Willing to be randomized Willing to drive to a nearby lab for blood draws 3x during the study over the course of 20 weeks (8-week intervention period followed by 12-week follow-up period) Taking sleep medications and/or over-the-counter sleep drugs/supplements (if any) on fewer than 3 nights per week and one of the following: 1) willing to maintain the same intake without change throughout the study time frame (i.e., 20 weeks) or 2) willing to discontinue if intake is prescribed as needed (PRN) by a physician throughout the study time frame (i.e., 20 weeks) Exclusion Criteria: Self-report meditation practice or meditative movement practice (i.e., yoga, tai chi, qi gong) of ≥60 min/week in past 2 months Reside outside of the United States of America Any planned change to a new pharmacologic therapy (i.e., new drug) for the treatment of their cancer diagnosis (excluding dose changes) Diagnosed with a sleep disorder except insomnia (≥2 positive categories on Berlin Questionnaire) Taking prescribed sleep medications and/or over-the-counter drugs/supplements (including drugs like NyQuil, Benadryl, and other antihistamine-based drugs) on ≥3 nights per week Any other diagnosed and uncontrolled medical or psychiatric condition Has a pacemaker Shift work schedule

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Calm Meditation<br>Participants assigned to the Calm group will be asked to complete a minimum of 10 minutes per day of meditation, at any time of day they choose for eight weeks. During weeks 1-4 participants in the Calm group will be asked to complete the introductory 30-day program How to Meditate. Weeks 5-8, participants will be asked to complete one daily meditation that may include the Daily Calm, a different 10-minute mindfulness meditation each day, or a meditation from a various series of meditations (e.g., loving-kindness, seven days of managing stress). Participants will have complete autonomy to choose the meditation. After the participant has completed their daily meditation, participants will also be able to use the app content more broadly based on their preference. | Behavioral: Calm Meditation<br>* This is the active intervention group.<br>* Other names: CALM;|
| Active Comparator: Health Education Podcast<br>Similar to the Calm group, participants in the POD group will listen to a minimum of 10 minutes per day of a health education podcast delivered via a mobile app for eight weeks. Content was carefully chosen to exclude any recommendations for sleep, meditation, or for mindfulness-like principles or practice. A library of podcasts is available on the app. Participants are able to select the podcast based on title, time or both in an effort to mirror the delivery of the meditations in the Calm group. | Behavioral: Health Education Podcast<br>* This is the active comparator/control group.<br>* Other names: POD;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sleep Disturbance (subjective) | Sleep disturbance will be measured with the Insomnia Severity Index (ISI). Total scores range from 0 to 28 with scores 8 to 14, and ≥15 indicating subclinical and moderate-to-severe insomnia symptom severity, respectively. | Changes in sleep disturbance will be measured at baseline, week 2, week 4, week 6, week 8, and week 20. Total scores range from 0 to 28 with scores 8 to 14, and ≥15 indicating subclinical and moderate-to-severe insomnia symptom severity, respectively. | 
| Sleep Disturbance (subjective) | Sleep disturbance will be measured with the Patient Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance Short Form 8b. This form consists of 8 items in a 1-5 Likert scale. The measure generates a total summed score, which is then converted to a standardized t-score. | Changes in sleep disturbance will be measured at baseline, week 8, and week 20. This form consists of 8 items in a 1-5 Likert scale. The measure generates a total summed score, which is then converted to a standardized t-score. | 
| Sleep Disturbance (subjective) | Sleep disturbance will be measured with the Patient Reported Outcomes Measurement Information System (PROMIS) Sleep-Related Impairment. This form consists of 8 items in a 1-5 Likert scale. The measure generates a total summed score, which is then converted to a standardized t-score. | Changes in sleep disturbance will be measured at baseline, week 8, and week 20. This form consists of 8 items in a 1-5 Likert scale. The measure generates a total summed score, which is then converted to a standardized t-score. | 
| Sleep disturbance (subjective) | Sleep disturbance will be measured with an investigator-developed weekly sleep diary | Changes in sleep disturbance will be measured weekly throughout the 8-week intervention period and once again during the week 20 follow-up period. | 
| Sleep disturbance (objective) | Sleep disturbance will be measured with wrist actigraphy | Changes in sleep disturbance will be measured weekly throughout the 8-week intervention period and once again during the week 20 follow-up period. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inflammation | Inflammation will be measured with blood serum cytokines (C-reactive protein, TNF-a, IL-6, IL-8) | Changes in inflammation will be measured at baseline, week 8, and week 20. | 
| Fatigue (subjective) | Fatigue will be measured with the Patient Reported Outcomes Measurement Information System (PROMIS) Adult Cancer Fatigue Short Form 7a. This form consists of 7 items in a 1-5 Likert scale. The measure generates a total summed score, which is then converted to a standardized t-score. | Changes in fatigue will be measured at baseline, week 8, and week 20. | 
| Anxiety (subjective) | Fatigue will be measured with the Patient Reported Outcomes Measurement Information System (PROMIS) Emotional Distress-Anxiety Short Form 7a. This form consists of 7 items in a 1-5 Likert scale. The measure generates a total summed score, which is then converted to a standardized t-score. | Changes in anxiety will be measured at baseline, week 8, and week 20. | 
| Depression (subjective) | Fatigue will be measured with the Patient Reported Outcomes Measurement Information System (PROMIS) Emotional Distress-Depression Short Form 8a. This form consists of 8 items in a 1-5 Likert scale. The measure generates a total summed score, which is then converted to a standardized t-score. | Changes in fatigue will be measured at baseline, week 8, and week 20. |