Addressing Psychological Distress Symptoms Among Serious Illness Survivors of a Viral Pandemic With a Completely Self-directed, Symptom-responsive Mobile Mindfulness Intervention: a Randomized Controlled Trial
Phase: NA
Conditions: COVID-19, Cardiorespiratory Failure
Sponsor: Duke University

Pro00106306: Addressing psychological distress symptoms among serious illness survivors of a viral 
pandemic with a completely self-directed, symptom-responsive mobile mindfulness intervention 
 
Protocol version: 3.0  
Dated: 05 Mar 2021 
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Clinical Protocol Synopsis 
 
 
1.  Title  
Addressing psychological distress symptoms among serious illness survivors of a viral pandemic with a 
completely self-directed, symptom-responsive mobile mindfulness intervention (NCT identifier pending) 
 
2.  Background  
Rigor of prior research: Cardiorespiratory failure patients suffer from persistent psychological 
distress—as COVID-19 patients likely will.1,2   
>2 million patients are treated in ICUs annually in the US for cardiorespiratory failure caused by 
pneumonia, sepsis, and congestive heart failure, among others.3  After discharge, patients experience 
clinically important symptoms of psychological distress—depression, anxiety, and post-traumatic stress 
disorder (PTSD)—symptoms that are both common (50-70%) and persistent.4-11  Pneumonia, the 
second-most common cause of hospitalization, places its survivors at high risk for persistently 
worsened health status and lasting depression, anxiety, and PTSD symptoms.  Currently acute 
infection with the severe acute respiratory syndrome novel coronavirus 2 which leads to coronavirus 
disease 2019 (COVID-19) is causing the largest pandemic of pneumonia in over 100 years.12,13  
COVID-19 is a mild disease for ~80% of patients, but 10-20% of patients are hospitalized with 
pneumonia.  Of those hospitalized, up to 88% require respiratory support such as mechanical 
ventilation.14,15  COVID’s specific post-hospital outcomes have not been clearly described; not even 100 
days have transpired since the disease was first defined.  Yet since patients will be recovering from 
severe disease during a global state of emergency and economic stress, COVID-19 likely puts them at 
even higher risk of distress than other forms of cardiorespiratory illness.1,2   
 
Conceptual orientation and rigor of proposed research:  The LIFT mobile mindfulness 
intervention is a scalable approach for improving COVID-19 patients’ psychological distress.  
The COVID-19 pandemic represents a unique threat to patient-centered care given new norms of 
‘social distancing,’ limited healthcare resources that serve as barriers to distress assessment and timely 
treatment, and economic devastation of those impacted by it.16-18  Clinical resources are stretched thin 
as health systems are overwhelmed with the stresses of caring for massive numbers of COVID-19 
patients, forcing the cancellation of outpatient clinics.  Most research institutions have banned study 
staff from conducting clinical research that includes direct patient contact.  These barriers require a 
novel approach that we believe can be effectively provided by this Supplement proposal.19 
 
LIFT is ideally positioned to overcome barriers to both the timely delivery of mind-body therapy as well 
as research participation during a pandemic like COVID-19.  Its tested mindfulness content promotes a 
practice of non-judgmental awareness that can alleviate distress by uncoupling emotional reactions and 
habitual behavior from unpleasant symptoms, thoughts, and emotions—content that improves 
symptoms of depression, anxiety, and PTSD.20-24  LIFT’s ‘touchless deployment’ allows automated 
screening, consenting, intervention activation, and data collection without direct patient contact.  
Additionally, LIFT is a self-guided mobile app that works on any device, giving it the flexibility and 
scalability required in a pandemic.  LIFT is a scalable solution for overcoming barriers to addressing 
COVID patients’ distress—and our research network is ideal for conducting an RCT to test it.  
 
3.  Focus of the Study and Specific Aims   
BLUE CORAL and LIFT COVID study designs (Figure) 
LIFT COVID is a 300-participant, two-arm, parallel groups RCT with 6-month follow up nested within 
the NHLBI PETAL Network’s BLUE CORAL observational study of patients hospitalized with 
cardiorespiratory manifestations of COVID-19.  The PETAL data coordinating site, the University of 
Michigan, will screen participants, conduct informed consent, and conduct all follow up interviews.  
Participants with symptoms of depression (PHQ-9 ≥5) 1 month after hospital discharge will be 
randomized to either the LIFT intervention (Standard Dose, App-based Symptom Response, No intro 

Pro00106306: Addressing psychological distress symptoms among serious illness survivors of a viral 
pandemic with a completely self-directed, symptom-responsive mobile mindfulness intervention 
 
Protocol version: 3.0  
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Call) or usual care control.  Follow up interviews 
will be done 1, 3, and 6 months post-discharge 
(i.e., 0, 2, and 5 months post-randomization), as 
per BLUE CORAL’s current timeline.   
 
Specific aims for LIFT COVID RCT 
Aim 1: In an RCT nested within the NHLBI’s 
PETAL BLUE CORAL cohort study of 1,500 
planned participants, to test the clinical impact of 
LIFT (n=150) vs. usual care control (n=150) 
among recently discharged patients recovering 
from serious COVID-19 infection. 
   Hypothesis:  Compared to control at 3 months 
post-discharge (i.e., 2 months post-
randomization [T2]), LIFT will reduce symptoms 
of depression (primary outcome; Patient Health 
Questionnaire-9 [PHQ-9] as well as secondary 
outcomes of anxiety (General Anxiety Disorder 
[GAD-7]) and PTSD (Post Traumatic Stress 
Scale [PTSS]).   
 
Aim 2: In an RCT nested within the PETAL 
BLUE CORAL cohort study, to test the clinical 
impact of LIFT (n=150) vs. control (n=150) at 6 
months post-discharge. 
   Hypothesis:  Compared to control, LIFT will reduce symptoms of depression, anxiety, and PTSD and 
6 months post-discharge.   
 
Aim 3:  Among RCT intervention participants, explore barriers and facilitators to LIFT intervention 
implementation and dissemination in the context of a pandemic.  
   Approach:  Using qualitative analysis of semi-structured interviews from 25 purposively sampled 
participants enrolled from Supplement Aim 1, we will explore perceptions about barriers to accessing, 
using, and applying LIFT effectively in a pandemic.  This could improve LIFT processes in the future. 
 
4.  Study population 
4.a. BLUE CORAL eligibility 
Eligible BLUE CORAL patients will be enrolled within 72 hours of hospital admission or COVID-19 
confirmation by PCR.  Target enrollment is 1,500 patients overall. If enrollment is slow across the Network, 
alterations may be made in the approach outlined above. Patients or legal next of kin will be approached to 
engage in the process of informed consent.   
 
Inclusion criteria:  
1. Adult hospitalized within 14 days of a positive PCR test for COVID-19  
2. Evidence of acute COVID-19, with fever or respiratory manifestations, as characterized by signs 
and symptoms such as cough, dyspnea, tachypnea, hypoxemia, and infiltrates on chest 
imaging.  
 
Exclusion criteria:  
1. Lack of informed consent  
2. More than 72 hours of continuous hospitalization.  
3. Comfort care orders in place at the time of enrollment and/or unexpected to survive for 24 hours  
4. Prisoners  

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pandemic with a completely self-directed, symptom-responsive mobile mindfulness intervention 
 
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5. Previous enrollment in BLUE CORAL  
 
4.b. LIFT COVID eligibility 
There will be 300 BLUE CORAL patients selected for detailed post-hospital assessment—these will be the 
target population for the LIFT COVID RCT.  If there are more eligible patients, patients may be selected 
randomly or according to enrichment strategies which will be informed by the composition of the cohort.  
Informed consent will be obtained by telephone for these potential participants.  
 
Inclusion criteria: 
1. Enrolled in BLUE CORAL 
2. Survival to hospital discharge 
2. English-speaking 
3. Domiciled with access to a working telephone and smartphone, tablet, or computer with wifi or internet 
connection 
4. Absence of severe dementia or severe functional disability before hospitalization or at time of 1 month 
post-discharge interview 
 
Exclusion criteria:  
1. PHQ-9 <5 at time of interview 1 month post-discharge  
2. Suicidal ideation at time of interview 1 month post-discharge 
 
5.  Screening  
PETAL research staff will identify potentially eligible COVID+ patients hospitalized during the study period 
using medical records and lists maintained for clinical operations.  A log of hospitalized COVID+ patients 
during the study period will be compiled by participating sites. This log will include simple information: 
patient name, medical record number, age, sex at birth, date of admission, admission location (ward or 
ICU), race and ethnicity, and BLUE CORAL enrollment or reason for non-enrollment. This log will be used 
to describe the relationship between enrolled patients and the larger population. Patient names and 
medical record numbers from this log will only be used at the local sites and not transmitted to the Clinical 
Coordinating Center (CCC). Research staff will use the medical records for patients on the log to determine 
study eligibility.  Patient names and medical record numbers will be removed from screening logs, which 
will then be uploaded by each site into REDCap.  This information will be used to describe basic 
characteristics of the entire population of patients with COVID-19 hospitalized at participating hospitals 
during the BLUE CORAL study period.  If there are multiple patients eligible for BLUE CORAL on a single 
day, coordinators will prioritize ICU patients first.  The screening log will be updated with the results: 
enrolled, declined, not attempted, ineligible.  
 
6.  Process of Obtaining Informed Consent  
6.a. BLUE CORAL 
Overview  
Prior to conduct of study procedures, informed consent will be obtained from the patient or from a 
surrogate decision maker if the patient lacks decision-making capacity.  In some instances, bringing a 
paper consent form and pen to the bedside of a patient with known or suspected COVID-19 and then 
taking these out of the room would violate infection control principles and policies.  Given the infectious risk 
from COVID-19 and potential shortages of personal protective equipment (PPE), there is a moral and 
practical imperative to minimize face-to-face contact between patients and non-clinical personnel.  The 
current epidemic also presents unique challenges to obtaining consent from participant’s legally authorized 
representative (LAR).  To minimize infectious risk, many institutions are not allowing visitors to enter the 
hospital.  Furthermore, the LAR is likely to have been exposed to the patient and may therefore be under 
self-quarantine at the time of the informed consent discussion.  
 

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Therefore, in addition to the traditional approach of an in-person consent discussion and signed paper 
informed consent document, we will allow use of “no-touch” consent procedures for this trial.  Below, we 
outline two examples of no-touch consent procedures that may be used: (a) a paper-based approach; and 
(b) an electronic/e-consent approach.  
 
Paper-based approach  
1. The informed consent document is delivered to the patient or LAR.  
a) If the patient or LAR is on-site, the informed consent document many be delivered to the 
patient or LAR either by research staff or by clinical staff  
b) If the LAR is off-site, the informed consent document may be emailed, faxed, or otherwise 
electronically transferred to the LAR (method dictated by institutional policy)  
2. Research staff discuss the informed consent document with the patient or LAR either in- person or 
by telephone or videophone. This step confirms subject/LAR identity.  
3. If the patient or LAR decides to consent to participate, the patient or LAR signs the paper copy of 
the informed consent document.  
4. A photograph is taken of the signature page of the informed consent document and uploaded into 
the electronic database (e.g. REDCap).  
a) If using the patient’s device (such as a patient’s personal cellular phone), a survey link can 
be sent to their device to allow direct upload of the image into the electronic database (e.g. 
REDCap).  
b) If using a staff device, it must be approved to store PHI by the local institution. In that case, 
research personnel can take a photograph of the signature page of the informed consent 
document either directly or through the window or glass door leading into the patient’s room. 
The photograph can then be uploaded into the electronic database. If a staff device is taken 
into the patient’s room to take a photograph it must be able to be disinfected according to 
local institutional practices.  
5. Research staff and witness provide signatures within the electronic database (e.g. REDCap) 
confirming their participation in the informed consent process.  
6. The patient or LAR retains the paper consent document. The image of the signature page may be 
printed and bundled with a copy of the blank informed consent document for research records.  
 
Electronic / e-consent approach  
1. The electronic informed consent document is opened on a research device or a link for the 
electronic informed consent document is sent to the patient’s or LAR’s device.  
2. Research staff discuss the informed consent document with the patient or LAR either in person or 
by telephone or videophone. This step confirms subject/LAR identity.  
3. If the patient or LAR decides to consent to participate, the patient or LAR signs the electronic 
informed consent document. This signature may be either:  
a) an actual signature (often tracing a finger on the screen) OR  
b) a username and password specific to the individual signing  
4. Research staff and witness provide signatures within the electronic database (e.g., REDCap) 
confirming their participation in the informed consent process.  
5. The image of the signature page may be printed and bundled with a copy of the blank  
 
informed consent document for research records.  
6. If a hospital device is provided to facilitate electronic or paper-based consent, that device will be 
disinfected according to institutional protocols and removed by research staff or clinical staff during 
the next entry into the patient’s room.  
 
This approach complies with relevant regulations and sub-regulator guidance at 45 CFR 46.117, 45 CFR 
164.512, 21 CFR 11 Subpart C (11.100–11.300), https://www.hhs.gov/ohrp/regulations- and-

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policy/guidance/use-electronic-informed-consent-questions-and-answers/index.html, 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/informed-consent  
 
Post-hospital procedures  
Patients who provided informed consent during hospitalization will be asked to confirm their interest in 
participation verbally during follow up calls.  Patients selected for participation in post- hospital surveys who 
were unable to provide informed consent (enrolled via surrogate consent and unable to engage in informed 
consent before hospital discharge) will participate in the informed consent process by telephone.  Those 
agreeing will provide verbal consent.  The same process will be used for family members selected to 
participate in post-hospital procedures.  
 
6.b. LIFT COVID RCT 
Screening 
1. At the time of the 1 month (T1) BLUE CORAL post-discharge interview, the FUNCTION staff will 
conduct the PHQ-9 survey.   
2. For those with a PHQ-9 score ≥5, the research staff will discuss the informed consent document 
with the patient by telephone or videophone.  
 
Informed consent 
Verbal process 
1. During the phone call, a formal DUHS Central IRB-approved telephone script for informed consent 
will be followed for LIFT COVID by the FUNCTION staff. 
2. If the patient decides to consent to participate, the study team will record the participant’s name, 
their contact information, and the date and time of consent.  This information will be entered in the 
study data system. 
3. If the patient requests to be called back at a different time to discuss consent, a study team member 
will do so.  Per the patient’s direction, the study team will follow the protocol for either the verbal 
process above or the electronic consent process described below. 
4. If the patient declines, this will be noted in the study database. 
 
Electronic consent process 
1. For those who prefer completing electronic informed consent, they will do so by following a unique 
URL sent via an email to a study-specific REDCap e-consent form.  Their signature will be done by 
tracing their finger on the screen.  The e-consent form will be retained in the research data system. 
2. Research staff and witness provide signatures within the electronic database confirming their 
participation in the informed consent process per Duke policy.  
3. A copy of the signed/dated consent form will be provided to the participant.  
 
There may be instances related to obtaining informed consent that the FUNCTION staff is unable to 
complete the outlined processes above. Should this occur, the FUNCTION staff will communicate with 
sister sites, Oregon Health & Sciences University (OHSU) and University of Colorado-Denver (UCD). 
OHSU and UCD may be asked to complete the recruitment and informed consent process, as well as 
initiate app registration as further outlined in the sections below.  
 
7.  Data Collection  
7.a. BLUE CORAL data collection 
BLUE CORAL includes data collection from enrolled patients’ clinical records. There are three types of 
forms for each study: admission (hospital / study day 1), daily, and discharge.   
 
The case report form (CRF) is built in REDcap which can be imported as a local instance or centrally 
through the PETAL CCC.  Since there may be times when study personnel are mandated to work from 

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pandemic with a completely self-directed, symptom-responsive mobile mindfulness intervention 
 
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home due to the ongoing pandemic, BLUE CORAL has many study procedures that are designed to allow 
off-site completion.  All elements that contribute to the COVID ordinal outcome scale are included in daily 
and summative data collection.  Manual data entry of all elements into REDCap may not be required  
depending on the site's ability to extract data from the EMR.  
 
The BLUE CORAL study will obtain pre-hospital information from patients or their caregivers before 
hospital discharge.  The survey consists of questions regarding functional status and health-related quality 
of life.  PETAL study staff members are familiar with the conduct of these surveys as they were used 
successfully in the ROSE RCT.  With high severity of illness, infection control precautions, and absence of 
family visitation, we anticipate that survey completion will be difficult.  Therefore, we have developed 
multiple approaches to survey completion (telephone, tablet computer, or email with either patients or 
families) and will attempt to complete as able. 
 
BLUE CORAL patients who survive hospitalization, speak English, are domiciled, and did not have 
severe dementia or severe disability before hospitalization may be eligible to enter the post-hospital 
follow-up study (BLUE CORAL).  This study will be conducted by the FUNCTION team at the University 
of Michigan, led by Dr. Jack Iwashyna, using protocols developed and executed in the PETAL Network 
ROSE and ongoing CLOVERS studies.  Sister sites, Oregon Health & Sciences University (OHSU) and 
University of Colorado-Denver, led by Drs. Terri Hough and Marc Moss, respectively, may be asked to 
conduct the study visits as needed. Post-hospital follow-up will occur by telephone at 1, 3 and 6 months 
after hospital discharge (Table 1).  Patients will provide consent for continued involvement at the time of 
the first call.   
 
These post-hospital assessments will allow BLUE CORAL to measure the levels and rates of recovery 
on cardio-pulmonary symptoms as well as the key domains outlined in the NHLBI R24-funded 
“Improving Long-Term Outcomes” Program; to determine risk factors associated with poor outcomes; to 
assess the burden of COVID-19 recovery primary spouse or family caregiver of cohort members, 
stratified by whether the spouse themselves had COVID-19 or not; and to evaluate the association of 
the COVID-19 Outcome Score with patient- centered outcomes.  
 
7.b. LIFT COVID Surveys 
As shown in Table 1, participants enrolled in the LIFT COVID intervention arm will also complete the PHQ-
9 survey weekly within the LIFT mobile app for the duration of the 4-week intervention. 
 
7.c. List of all BLUE CORAL and LIFT COVID surveys 
Inpatient 
Table 1: Data collection timing and content for BLUE CORAL and LIFT RCT participants.
 
Hospital 
1 month* 
(T1) 
During 
intervention1, 2 
3 months* 
(T2) 
6 months* 
(T3) 
Contact info 
X 
X 
 
X 
X 
PHQ-9 depression (primary outcome) 
 
X 
X 
X 
X 
GAD-7 anxiety 
 
X 
 
X 
X 
EQ-5DL quality of life 
X 
X 
 
X 
X 
ADL / IADL limitations 
X 
X 
 
X 
X 
Financial strain 
X 
X 
 
X 
X 
Cardiopulmonary symptoms 
 
X 
 
X 
X 
Cognitive function (MOCA/AD8, Hayling) 
 
X 
 
X 
X 
Rehospitalization 
 
X 
 
X 
X 
* Timing is from the time of hospital discharge 
1 Collected via the Lift mobile app weekly 
2 These data collected only for LIFT RCT participants.  This will be done via the app platform. 

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• Recent living status (1 item) 
• Days hospitalized in month prior to COVID-19 admit (1 item) 
• EQ-5D-5L baseline (5 items) 
• Activities of Daily Living (ADLs) and Instrumental ADLs baseline (13 items)  
• AD8 (8 items, completed by caregiver) 
• Household Financial Strain (7 items) 
• Occupation and Industry (2 items) 
• Number of People in Household (1 item)  
 
Post-hospital patient surveys  
• COVID-19 Recovery (1 item) 
• EQ-5D-5L (5 items) 
• Activities of Daily Living (ADLs) and Instrumental ADLs (13 items)  
• Financial Toxicity (12 items) 
• Cardiopulmonary symptoms and respiratory support (13 items) 
• Patient Health Questionaire-9 (9 items) 
• Generalized Anxiety Disorder-7 (7 items) 
• Healthcare utilization (1 item) 
• Demographics (2 items) 
• Montreal Cognitive Assessment MOCA-Blind 
• Hayling Test of Executive Function 
• Select Current Medications, matched to those collected in-hospital  
 
8.  Randomization.  
Figure 1 shows the general approach to screening, informed consent, and randomization.  PETAL sites will 
obtain informed consent for the BLUE CORAL observational study.  At the time of the 1-month post-
discharge follow up call from the University 
of Michigan, potential participants will be first 
screened on the for sufficient distress (i.e., 
PHQ-9 ≥5). For those who meet the cutoff, 
the staff will describe the LIFT trial and 
obtain informed consent by phone.  For 
those who provide informed consent, the 
delegated study staff will enter the data 
required for randomization (contact 
information, stratification variable data) into 
the Shibboleth password-protected Lift app 
platform study staff dashboard.  This will 
enable auto-randomization by the LIFT 
platform.  Randomization will be stratified by 
age, gender, and baseline PHQ-9 score. 
 
At this point, an automated SMS text 
message and/or email (per user preference) 
will be sent to the participant that alert them 
to their treatment group.  For intervention 
group participants, it will also provide a link 
to download the LIFT app platform and a 
unique ID code to activate it.  After download 

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pandemic with a completely self-directed, symptom-responsive mobile mindfulness intervention 
 
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and activation with the unique ID, the participant’s experience will be automated.   
 
9.  LIFT COVID RCT procedures 
Aims 1 and 2.   
LIFT is a self-directed mobile app platform based on a solid conceptual model that guides participants 
through a 1-month program.  LIFT content includes 4 weekly app-based sessions as previously tested in a 
pilot RCT (NCT02701361).21  Each session is composed of three parts:  1. Video presentation describing 
rationale (3-5 min.), 2. Audio guided meditation (8-10 min.), and 3. Other relevant in-app exercises (e.g., 
tips to help apply mindfulness to daily life).  Each week a participant completes the PHQ-9 depression 
symptom survey within the app.  While the parent U01 factorial trial is comparing 8 versions of LIFT that 
differ on 3 factors (NCT04038567), the LIFT COVID RCT will use the version of LIFT that includes no 
introduction call, app-based response to symptoms changes during the intervention period, and standard 
dose.  The app-based approach to non-responders, defined as those whose PHQ-9 score has increased in 
comparison to the previous week or whose PHQ-9 score is ≥20, uses the app's logic to display hovering 
messages and notifications within the app that may be applicable to the user.  Depending on whether 
emotional or somatic depression symptoms are dominating the PHQ-9 score for the individual, a unique 
video is shown within the app that features the study interventionists leading a brief exercise in which the 
participant is coached by the interventionist in the application of mindfulness for the symptoms the 
participant has endorsed.  The app-based approach to non-responders has 8 unique videos, 2 for each 
week (i.e., one tailored to emotional symptoms, one tailored to somatic symptoms).   
 
Aim 3 procedures (cross-sectional focus groups) 
The goal of Aim 3 is to understand the barriers and facilitators to the successful use of the LIFT app from a 
patient's perspective within the context of a pandemic.  We will use a stratified purposive design to sample 
25 participants (~2 / mo.), a number sufficient for theme saturation,25 after 3 months post-discharge.  The 
procedures will include a ~30-minute semi-structured one-on-one interview conducted by phone (based on 
participant preference and availability) by an experienced coordinator that will explore app access, use, 
and content.26,27  Theoretical sampling will ensure sufficient variability in characteristics that may influence 
experiences, stratifying cases by response to LIFT (high vs. low), LIFT use (high vs. low), demographics 
(age, gender), and baseline distress (moderate vs. high).28-31   
 
10.  Statistical design, analyses, sample size, and power:  
Aims 1 and 2  
The goal of the parent U01 trial analysis is to determine which LIFT components (i.e., factors) have the 
greatest salutary effects on MOST optimization criteria of feasibility, usability, and clinical impact.   
 
Analyses for the LIFT COVID RCT’s Aims 1 and 2 are designed to compare the clinical impact on 
psychological distress symptoms (depression, anxiety, PTSD) LIFT (n=150) vs. control (n=150) among 
COVID-19 patients.  All participants will be analyzed by their assigned group, regardless of adherence or 
crossover status.  Briefly, we will test the primary study hypothesis that the PHQ-9 score is lower (i.e., 
fewer depression symptoms) for LIFT recipients compared to control 3 months post-discharge with a 
general linear model using SAS PROC MIXED (SAS Institute, Cary NC).  An unstructured covariance 
matrix will be specified to account for the correlation between longitudinal repeated measures.  Similar 
analyses will be performed in Aim 2 for the GAD-7 and PTSS, as well as for all other outcomes at 3 and 6 
months.32,33  Procedures for missing data will include (as needed) sensitivity analyses, multiple imputation 
PROC MI),34 and estimates combined using Rubin’s rules as implemented in PROC MIANALYZE.35,36 
 
Goal and procedures for Aim 3 
Supplement Aim 3 will add an additional 25 COVID-positive LIFT recipients to the 75 included in the parent 
U01’s Aim 3, with the goal of understanding barriers and facilitators to the successful use of the LIFT app in 
a pandemic.37-39  We will use a stratified purposive design to sample 25 participants, a number sufficient for 

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theme saturation.40  The procedures will include a 30-minute semi-structured telephone interview 
conducted by an experienced coordinator to explore app access, content, and use.26,27  Theoretical 
sampling will ensure variability in potentially influential characteristics: response to LIFT (high vs. low), 
demo-graphics (age, race, gender), and baseline distress (moderate vs. high).28-31  Analyses will be nearly 
identical to the U01 and will use modified grounded theory methods (e.g., open and axial coding, 
consensus building on codes, member checking) 28,30,31,41,42 to inductively and iteratively develop 
frameworks.43-46   
 
Sample size and power considerations 
For Supplement Aim 1, we will randomize 300 patients.  Even with a 40% dropout rate (i.e., 180 at 3 
months) and conservative assumptions (SD=6.0, ρ=0.5, two-sided test, type-I error of 5%), this sample size 
will provide a power of 80% to detect a differential between-group PHQ-9 improvement at 3 months as 
small as 2.5 units, substantially less than the minimal clinically important difference (MCID) of 5.0 units.47  
Calculations were based on mixed-models tests for a difference in slopes using PASS 16 Software 
(v16.0.5; Kaysville UT).   
 
11.  Subject Participation Duration:  It will require 5 months for participants to complete the entire study 
from the time of randomization, including the month-long intervention and follow up surveys.   
 
12.  Study Duration:  We estimate that from the time the RCT opens to enrollment it will require 1 year to 
complete all study activities. 
 
13. Costs to the Subject:  There are no costs to participants. 
 
14.  Compensation 
Participants will receive $20 for each completed survey, up to a total of $60, for participation in the LIFT 
COVID study.  
 
15.  Risk-benefit assessment 
Potential risks 
It is possible that participants could experience a breach of privacy should their records be accessed 
unlawfully by an outside party.  Also, it is possible that participants may experience mild anxiety when 
answering survey questions, though we have not observed this in similar interventions such as LIFT or 
CSTEP.  However, we believe that involvement in this study will present no significant physical, 
psychological, financial, legal, or other risks.  Additionally, there is always the potential of a breach of data 
security, as is noted in any IRB-approved consent form.  However, we have a number of security features 
to protect these data that will be described below in Section 2.   
 
Adequacy of protection against risks  
Recruitment and informed consent procedures 
First, the Duke Institutional Review Board (IRB) will review and approve the study protocol before study 
initiation (as they did for our preliminary work conducted under Duke IRB Protocols #00062340, #00069031, 
and #00071161).  Informed consent (verbal, e-consent, or written) will be required from all participants.  
Second, we will use a standardized screening and enrollment protocol that respects participant privacy and 
rights.  Clinical research coordinators will approach patients to discuss the study at the time the BLUE CORAL 
participant is on the phone completing a BLUE CORAL survey.  This will be possibly be aided by a short IRB-
approved recruitment video we have produced and piloted for LIFT, similar to other highly rated videos our 
group has made for similar purposes in other clinical trials.  After following the verbal consent script, the clinical 
research coordinator will then obtain verbal informed consent from the participant.  If a patient wishes to do e-
consent, this procedure will be followed as described above in Section 6.B.  Potential subjects will have up to 
72 hours to consider enrollment.  For the clinical trial, we will take great care to present the treatment group 

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assignment possibilities (“like drawing a number out of a hat”) tactfully and with clearly stated equipoise in 
person, as we have done successfully in past ICU-based clinical trials.  A copy of the consent form will be 
emailed or mailed to participant (as they prefer) and the original maintained in the study data system (e-
consent) or in a secure location at the study site (mailed consent).  The study team will provide contact 
information for the PI.   
 
Protections against risk   
General oversight   
There are several ongoing mechanisms for monitoring the occurrence of adverse events.  The University of 
Michigan, Duke, Colorado, and Oregon investigators will perform day-to-day monitoring of the study activities 
at their sites as they have done in many other trials and studies involving similar participants.  The Principal 
Study Investigator, Dr. Cox, has demonstrated in research to date involving nearly 1,500 participants that he 
keeps careful records of patients' whereabouts and health status.  Careful monitoring of all persons entering 
the study will minimize attrition and will ensure the clinical safety of these patients.  This monitoring is 
facilitated by a telephone number (PI's cell phone) and email address (LIFTCOVID@duke.edu) provided to 
participants upon entry into the study to report concerns related to study participation, weekly meetings 
between the clinical research coordinators and co-investigators to discuss study progress and any adverse 
events, and direct supervision of the study by the PIs.   
 
Plans to prevent coercion of patients and to ensure voluntary participation 
We will strive to create an environment free of any coercive practices for patients. We will stress that study 
involvement is absolutely voluntary and that choosing to participate or not participate will not affect their care in 
anyway. In addition, we will utilize the standardized 2-minute informational video (lift.duke.edu/COVID), which 
has been used successfully in the LIFT trial to describe treatment groups and ensure a similar approach 
across sites.   
 
Specific longitudinal participant oversight plans for severe psychological distress (including suicidal ideation)— 
research coordinators and the study data system 
Given the difficult situations faced by COVID patients, we recognize that there is a slight risk that some 
participants may become distressed completing questionnaires or viewing study materials, as mentioned 
above.  Additionally, given the extreme stresses of the critical illness experience, participants may even 
endorse suicidal ideation.  We will take the following measures to prevent any negative reactions as well as 
effectively manage any serious distress that occurs:  
 
(1)  All of the in-person and telephone-based data collection sessions will be conducted by highly trained 
research coordinator professionals who are sensitive to the issues that arise.  
 
(2)  Clinical research coordinators will emphasize to participants that any interviews or other study interactions 
are participant-controlled.  Thus, participants will be instructed that they are in control over what they share and 
generally how long they discuss any topic that is addressed.   
 
(3)  Participants will be told that they can discontinue an interview at any time and that they are also free to 
reschedule an interview or treatment session at any time within the week.   
 
(4)  Overall, we are very sensitive to the common and pervasive nature of psychological distress among 
COVID survivors and are experienced in discussing these issues with them.  There is also a potential risk for 
identifying underlying mental health issues through the LIFT sessions, telephone calls, and survey responses.  
For issues such as passive suicidal ideation or symptoms of depression, anxiety, or PTSD, an informational 
sheet will be provided with contact numbers for additional mental health services.  Additionally, at the 
beginning of the program, all subjects will be informed that the training program may uncover unresolved and 
distressing thoughts or feelings; and a list of resources will also be provided at that time. 
 

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(5) As a safety measure that we have used in past/current clinical research, the study team will be trained to 
monitor participants closely beyond just the parameters of questionnaire scores.  The study staff, including the 
trained clinical research coordinators and the therapist, will monitor participants closely during any interviews 
performed and will refer those with any concerning level of emotional distress and/or relationship distress to 
the PI to evaluate by phone.  This will be done immediately, particularly if there is staff concern about a 
participant who indicates suicidality.  Point #6 below describes PI actions that will follow. 
 
(6)  We have developed a specific protocol to manage any study participant who expresses suicidal thoughts in 
person, by telephone, or via the app at any point during the study.  All study participants will be informed of this 
suicidality response plan prior to signing the informed consent for their participation in the study.  The PI or 
trained CRC will complete the online Columbia Suicide Severity Rating Scale (C-SSRS) training, a 30-minute 
interactive slide presentation followed by a question-answer session.  The C-SSRS is scale that can delineate 
high, moderate, and low-risk levels.   
 
Our Suicidality Response Plan can be activated in two main ways.   
First, study staff (coordinators, therapists, investigators, PI) may have in-person or telephone interactions that 
concern them.   
 
Second, the study app system will automatically detect any endorsement of active suicidal intent in a 2-
step process that is contingent on the PHQ-9's item #9 (which evaluates suicidal thoughts) and the C-
SSRS item #4 (which evaluates intent by asking: Have you had these thoughts and had some intention 
of acting on them?) as shown here: 
PHQ-9 item 9 
response
Suicidal intent 
item response
Action by app system 
Action by team 
0 
n/a 
n/a 
n/a 
1, 2, or 3 (i.e.,  0)   
NO 
n/a 
n/a 
1, 2, or 3 (i.e.,  0)   
YES 
Alert to study manager, 
therapist, and PI
Immediately contact participant
 
If the participant is deemed to be at high risk for active suicidality based on direct interaction or the PHQ-9 item 
plus the C-SSRS item response, the app system will send an alert email and/or text message in real time to 
the study manager, the study therapist, and relevant site PI (no PHI included, only study ID).  One of these 
study staff will then immediately contact the participant.  Using the full C-SSRS, the trained staff will then help 
to assess the participant to determine if they endorse active suicidal ideation.  The trained staff will also 
determine if the participant is currently being treated by a mental health professional.  
 
If the participant is considered to be actively suicidal then at least one of the following plans will be followed 
depending on the location of the participant for each of the following situations: 
 
Situation 1. If the participant is with one of the study personnel [not expected to occur in the RCT]: 
 
a. The study personnel will notify the PI immediately  
 
b. The study personnel will either physically walk the subject to the emergency department, or call a 
Psychiatric Emergency services number relevant to the site as described above.  
 
Situation 2. If the participant is on the telephone: 
 
a. The study personnel will notify the PI immediately. 
 
b. The study personnel will stay on the telephone with the subject participant. 
 
c. The study personnel will immediately contact 911 to initiate an on-site rescue if such action is 
clinically indicated.  
 
d. The study personnel will stay on the telephone with the subject until EMS services have contacted 
the participant. 

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Situation 3. If there are any active suicidal concerns in any of the surveys (e.g., PHQ-9 above): 
 
a. The study data system will notify the PI and Study Manager immediately. 
 
 
b. The study personnel will then contact the honest broker to de-identify the participant information.  
 
c. Next, the study personnel will contact the participant by telephone. 
 
d. The study personnel will stay on the telephone with the subject participant. 
 
e. The study personnel will use a different telephone line to immediately contact 911 to initiate an on-
site rescue if action is clinically indicated. 
 
f. The study personnel will stay on the telephone with the subject until EMS services have contacted the 
participant. 
 
If the participant if determined to be actively suicidal and require immediate medical therapy, they will be 
withdrawn from the study. 
 
If the patient is deemed not to be actively suicidal, they will be given contact information for the National 
Suicide Prevention Lifeline (1-800-273-TALK), a free, 24-hour hotline available to anyone in suicidal crisis or 
emotional distress.  This will occur via the app for the intervention group and via email for control participants. 
 
(7)  As described in above, all concerns about participant safety will be discussed immediately with the PI 
including concerning, severe distress that does not involve suicidality.  For these situations, once an “alert 
situation” is known, the PI will refer the participant if needed (based on a PI-led phone call) to local 
psychological resources as we have done previously with this well-tested Distress Management Protocol used 
successfully by Dr. Cox in 3 past clinical trials involving family members that used psychological distress 
outcomes.  We will also make urgent and emergency referrals as needed based on information learned by any 
site PI on a site-by-site basis (see contact information above).  It is important to note that this system has been 
developed in full partnership with the Duke IRB, who approve it in its entirety and have described it as a model 
for future patient safety in Duke-based clinical research.  To date based on these studies that have included 
over 400 participants, we have found that <5% of participants will require a call from the PI during some point 
in the study period.  Of those, none have required referral to acute psychiatric care after a detailed interview 
from the PI.  After a disposition / solution has been made, both the resolution (and follow up) will be 
documented in the ‘contact log’ section of the data system for reporting to the DSMB.   
 
(8)  Finally, though there were no patient deaths during the LIFT COVID RCT follow-up period, we recognize 
that we are working with a seriously ill population that is at risk for death during follow up due to their 
underlying illness.  We are very sensitive to issues surrounding patient death in relation to study procedures 
and interviews.  We have dealt with this respectfully for years in our studies involving in-person, telephone, and 
app-based interviews and surveys.  On phoning any participant, we will initiate a conversation in a sensitively 
scripted manner to tactfully ascertain the patient’s vital status should a family member answer first.  If the 
patient has died, we will provide brief support.  If a patient states that they wish to drop out, we will respect that 
as well.  
 
Vulnerable populations.  We will not enroll patients from vulnerable populations (e.g., imprisoned persons, 
minors). 
 
Adverse events (AEs), serious adverse events, (SAEs) and unanticipated problems (UPs).  Our plan for AEs, 
SAEs, and UPs has been reviewed and accepted by the NIH.  As mentioned before, we recognize that there is 
a slight risk that some participants may become distressed when completing self-report measures or 
participating in interviews.  In our previous studies using similar self-report surveys (telephone, in person, or 
ePRO), we have encountered little resultant distress.  In fact, many participants have reported that they were 
relieved to be able to have a platform through which to reflect on such issues.  When necessary, participants 
who experience psychological distress related to completing questionnaires will be referred for appropriate 

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psychiatric or psychological care.  All participants will have access to a PI’s mobile phone number available 24 
hours a day (shown in the consent form).  If a telephone interview is required, it will be conducted by an 
experienced interviewer who has been trained to be sensitive to the nature of these issues.   
 
In this trial, we expect AEs to be extremely uncommon because it is a behavioral trial.  However, it is possible 
that participants could become distressed in an ICU setting in the event that their loved one dies or becomes 
more ill.  One particular symptom of note that will be considered an AE and reported to the IMC will be suicidal 
ideation as operationalized by responding to PHQ-9 item #9 (Thoughts that you would be better off dead or of 
hurting yourself in some way) with either ‘more than half the days’ or ‘nearly every day’ out of the preceding 2 
weeks. In this trial, we do not anticipate any SAEs because it is a behavioral trial.  A SAE in this trial would 
include a suicide attempt, a hospitalization, or death. All serious adverse events will be reported within the 
standard timelines required to these bodies as well as to the OHRP and the NIH/NCCIH.  AEs and SAEs will 
be reported to these agencies per their standard guidelines.   
 
While we do not anticipate any UPs because it is a behavioral trial that focuses on ICU patients, critical 
illness and its recovery process are unpredictable.  Unanticipated problems will be identified, discussed 
by the PIs, and resolved by group consensus. Therefore, should there be unanticipated problems 
observed we propose the following reporting process—itself framed by NIH guidelines.   First, the PIs 
and Duke University will include a written report that will be submitted to the NCCIH, the study DSMB, 
and the Central IRB that will describe the UP, the context, and the proposed corrective plan.  This 
written report will be provided within 1 week (unless it/they is/are also an SAE, in which case the 
timeline for SAE reporting will be followed).  The UP will also be forwarded OHRP using 
ohrp@osophs.dhhs.gov within two weeks of the event.  
 
Period and Frequency for Event Assessment and Follow-Up 
Unanticipated problems will be recorded in the data collection system throughout the study.  
The PI will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation.  At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  
Events will be followed for outcome information until resolution or stabilization. 
 
Characteristics of an Adverse Event 
Relationship to Study Intervention 
To assess relationship of an event to study intervention, the following guidelines are used: 
1. Related (Possible, Probable, Definite) 
a. The event is known to occur with the study intervention. 
b. There is a temporal relationship between the intervention and event onset. 
c. The event abates when the intervention is discontinued. 
d. The event reappears upon a re-challenge with the intervention. 
2. Not Related (Unlikely, Not Related) 
a. There is no temporal relationship between the intervention and event onset. 
b. An alternate etiology has been established. 
c.  
Expectedness of SAEs 
The Study PI and Independent Monitoring Committee will be responsible for determining whether an 
SAE is expected or unexpected.  An adverse event will be considered unexpected if the nature, 
severity, or frequency of the event is not consistent with the risk information previously described for the 
intervention.   
 
Severity of Event 
The following scale will be used to grade adverse events: 

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1. Mild: no intervention required; no impact on activities of daily living (ADL) 
2. Moderate: minimal, local, or non-invasive intervention indicated; moderate impact on ADL 
3. Severe: significant symptoms requiring invasive intervention; subject seeks medical attention, 
needs major assistance with ADL 
 
Reporting Procedures 
We have a strong plan for AE reporting and follow up.  First, we have a very robust monitoring system 
for psychiatric and emotional symptoms.  For all groups, we will know ‘alert’ values of depression, 
anxiety, and PTSD symptoms the second a questionnaire is completed.  For the mobile mindfulness 
study arm, we will also know depression / anxiety symptoms weekly as well.  For symptoms that are 
either great in total burden (i.e., total score is high), we will call the participant to check in.  For specific 
symptoms such as the suicidal ideation item in the PHQ-9 depression questionnaire, we will also call 
the participant and assess the severity of the situation, triaging them as appropriate to psychiatric 
support.  For other matters, the study interventionist will also have frequent telephone contact with most 
participants, and can also refer those with concerning symptoms.  Last, we have broadly placed our 
email addresses and phone numbers in all study materials and will encourage people to contact us 
regarding any issues. 
 
Since this is a psychosocial intervention, we do not expect study related physical issues to occur.  
Furthermore, there is no labwork involved.   
 
All deaths will be reported to NIH Program Officer and to the DSMB Chair within 72 hours of study’s 
knowledge of death.  For each patient who dies, a brief report containing the following variables will be 
provided: 
Age 
Principal diagnosis 
Number of comorbidities 
Admission APACHE II score 
Days since enrollment 
Brief description of circumstances surrounding death including expected or unexpected. 
 
Serious (fatal or life-threatening) SAEs that are unanticipated (i.e., not listed in the Data and Safety 
Monitoring Plan) and that are related to the intervention will be reported to the NIH Program Officer and 
to the DSMB Chair within 7 days of study staff’s knowledge of the SAE.  The summary of all other 
SAEs will be reported to NIH Program Officer and to the DSMB quarterly, unless otherwise requested 
by the DSMB.  Additionally, for SAEs, we will hold an all-investigator teleconference within 7 days.  The 
PIs will draft a description of the SAE and an action plan.  This will be passed on to the IRB, the NIH, 
and DSMB within 72 hours of the teleconference. 
 
Reporting for Multi-Center Trials 
The site PI must immediately report to the coordinating center PI (Dr. Cox) any serious adverse event, 
whether or not considered study related, including those listed in the protocol or investigator brochure 
and must include an assessment of whether there is a reasonable possibility that the study caused the 
event within 48 hours of PI awareness of the event.  
 
They must also report any unanticipated problems within the same timeframe.  The Site PI must also 
report any protocol deviations or violations to the coordinating center PI within 7 days of PI awareness.  
Participating centers must also submit all reports to their local IRB in accordance with their institutional 
policies.   
 

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Unanticipated Problem Reporting  
Incidents or events that meet the OHRP criteria for unanticipated problems require the creation and 
completion of an unanticipated problem report form.  OHRP recommends that investigators include the 
following information when reporting an adverse event, or any other incident, experience, or outcome 
as an unanticipated problem to the IRB: 
 
Appropriate identifying information for the research protocol, such as the title, investigator’s 
name, and the IRB project number; 
 
A detailed description of the adverse event, incident, experience, or outcome;  
 
An explanation of the basis for determining that the adverse event, incident, experience, or 
outcome represents an unanticipated problem;  
 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the unanticipated problem. 
To satisfy the requirement for prompt reporting, unanticipated problems will be reported using the 
following timeline:   
 
Unanticipated problems that are serious adverse events will be reported to the IRB, 
Independent Safety Monitor(s), and NCCIH within 7 days of the investigator becoming aware of 
the event.  
 
Any other unanticipated problem will be reported to the IRB, Independent Safety Monitor(s), and 
NCCIH within 14 days of the investigator becoming aware of the problem.  
All unanticipated problems should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), and OHRP within 
one month of the IRB’s receipt of the report of the problem from the investigator. 
Adverse Event Reporting of Non-IND Studies 
SAEs that are unanticipated, serious, and possibly related to the study intervention will be reported to 
the Independent Safety Monitor(s), IRB, and NCCIH in accordance with requirements.   
 
Unexpected fatal or life-threatening AEs related to the intervention will be reported to the NCCIH 
Program Officer, and Independent Safety Monitor(s) within 3 days of the investigator becoming 
aware of the event.  Other serious and unexpected AEs related to the intervention will be 
reported within 7 days. 
 
Anticipated or unrelated SAEs will be handled in a less urgent manner but will be reported to the 
Independent Safety Monitor(s), IRB, and other oversight organizations in accordance with their 
requirements. and will be reported to NCCIH on an annual basis.    
 
All other AEs documented during the course of the trial will be reported to NCCIH on an annual 
basis by way of inclusion in the annual report and in the annual AE summary which will be 
provided to NCCIH and to the Independent Monitors.  The Independent Safety Monitor(s) 
Report will state that all AEs have been reviewed. 
 
Privacy.  We will closely safeguard participant privacy regarding protected health and personal information.  
Study ID numbers, generated randomly at the time of enrollment, are linked in a separate app subsystem that 
contains patient names and medical record numbers.  Further, names, birthdates, telephone numbers, 
addresses, and medical record numbers will be stored securely as described in the RDSP and only accessible 
by trained staff listed on the delegation log.  The PIs will be unable to view data in the database because they 
will lack passwords to do so.  Data will be delivered to the Duke site from the University of Michigan and 
PETAL REDCap databases in a scheduled manner and with data use agreements in place with both the 
University of Michigan and the Massachusetts General Hospital (i.e., PETAL DCC; Figure 2).  Data will be 
transferred via a Duke Box password protected folder system.  These data will be delivered as CSV files for 
subsequent upload by the statistical team as analytical files (e.g., SAS).  No PHI is visible in any user interface, 
with the exception of the initial survey in which the participant will enter this identifying information.  Study 
participants cannot view data via the app system, only enter data (a 'one-way view'). Patients access this one-
way view app system via secure, PHI-free email or text links sent from our study RedCAP data system.  

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Language specifying the way we use and release data will be shown in the informed consent form as required 
by the IRB. 
 
Digital security.  The study digital infrastructure 
consists of a mobile (i.e., native) app and a separate 
RedCAP digital study database.  We take digital 
security very seriously and will follow institutional 
guidelines for safeguarding data, health information, 
and study results.   
 
All technology will be managed by the PIs in a 
collaborative manner.   
 
 LIFT app:  The LIFT app is a native app.  Our 
programming service providers, Pattern Health, 
endeavor to build technological solutions that 
preserve the privacy, confidentiality, and security of 
protected health information that may be part of 
health records or research datasets.  Protected 
Health Information (PHI) is handled according to 
appropriate Health Insurance Portability and 
Accountability Act of 1996 (HIPAA) Privacy and 
Security Regulations.  All staff who work with 
sensitive data are required to complete appropriate 
HIPAA training with periodic updates, complete 
human subjects and data privacy training, comply with site IT Security Policies, and agree to the provisions of 
the University Rules of Behavior and Sanction Policy.  All sites strive to implement reasonable security controls 
in its product builds guided by FISMA, HIPAA, and OMB Circular A-130, Appendix III.  
 
Data security is of the upmost importance for our study, particularly in providing a digital, online intervention for 
our participants.  Beyond the robust security that RedCAP provides, Pattern Health has implemented and 
maintains several security protocols and controls for apps as well.  Pattern Health has developed a formal 
information security program, with a named individual responsible for its overall execution.  Pattern Health also 
periodically conducts an information technology (IT) security risk assessment on its projects, maintains formal 
documented protocols for reporting security breaches, assesses and manages security risks associated with 
vendors and subcontractors, maintains employee on-boarding and off-boarding policies that protect study data 
and integrity, and ensures continuing employee awareness of and education on security policies, standards, 
and procedures.  In terms of development approaches to security, Pattern Health evaluates and installs 
security patches in a timely fashion, protects systems against self-propagating malware, maintains secure 
coding policies and practices, and utilizes standardized secure build processes to protect Pattern Health 
hardware that accesses customer networks, protecting confidential data against attack.  Any and all storage of 
confidential participant data on Pattern Health hardware is strictly prohibited, and the use of off-shore service 
providers and/or data center facilities is prohibited unless approved by client.  For our study, the native app 
application and supporting backend system that Pattern Health develops will be hosted securely per DHTS 
regulations. 
 
16.  Data management.  
16.a. BLUE CORAL data management 
Data collected by study staff will contain identifiers.  For transmission of data to the PETAL DCC, 
subjects will be assigned a unique study number.  Those subjects that consent to the post hospital 
follow up study will have contact information collected and shared with the FUNCTION group so that 

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they may be contacted for the study assessments.  BLUE CORAL data is designed to be shared in 
order to facilitate rapid knowledge generation and dissemination, including plans to contribute data to 
the WHO/ISARIC COVID-19 registry.  BLUE CORAL data, images, and biospecimens may be shared 
with other projects provided that human subjects’ protections are followed.  BLUE CORAL case report 
forms, data dictionaries, and REDCap builds will be available on the public-facing PETAL website.  The 
BLUE CORAL committee will work with the PETAL DCC and Steering Committee to create a solid 
approach to early data sharing that accelerates knowledge while minimizing potential threats of 
invasion of privacy. Sharing of data and biospecimens will be reviewed by the PETAL Network Natural 
History Committee and/or Pathogenesis Committee, according to current PETAL protocol.  
ISARIC data elements from all completed cases will be regularly shared with ISARIC’s Oxford Data 
Coordinating center.  The PETAL Network will receive reports from ISARIC describing numbers and 
features of the cases contributed.  In addition, these data will be easily shared with other efforts to 
understand COVID-19 and will be expeditiously made publicly available.  Data use agreements will be 
put in place between Duke and both the University of Michigan (BLUE CORAL) and the Massachusetts 
General Hospital (PETAL DCC).   
 
Data quality and consistency of approach to data collection is very important.  We will follow the 
previously successful approach to multi-faceted quality assurance which includes: (1) use of Manuals of 
Operation for training and reference, (2) regular meetings between local Investigators and study 
coordinators to answer questions and ensure consistency in evaluations across study sites, (3) 
conferences between all Investigators for the same purposes, (4) ongoing quality assurance review and 
training updates, (5) data entry into a database with extensive automated checks of data validity, and 
(6) ongoing review of descriptive statistics by Investigators with detailed review of selected data.  We 
will use best practice physical and electronic security and back-up procedures as well.  
 
16.b. LIFT COVID data management 
For all non-PETAL gathered data, LIFT study staff will complete electronic case report forms (eCRFs) 
securely integrated within the LIFT platform that includes an electronic database.  We will use a parallel 
study operations workflow tracking application to manage participants' contact history log, survey schedule, 
and recorded adverse events.  Study personnel will utilize these data systems to create scheduled reports 
on the trials’ conduct (e.g., study milestones) to enhance the study's quality.  We will monitor the quality 
and consistency of data in a number of ways.  Monthly data cleaning will be done by the Study Manager 
and statistical team using customized group-blinded reports that will identify missing, outlier, or nonsensical 
data at time points when remedying them is feasible. 
 
17.  Data & safety monitoring plan for LIFT COVID RCT 
Plans for assurance of compliance regarding adverse event reporting.  All sites require investigators to report 
adverse events (including serious adverse events) to the central Institutional Review Board (IRB) at Duke, their 
own site IRB, and the study Data Safety Monitoring Board (DSMB) on both a per case and an annual basis.  
Also, all adverse events are reported as part of NIH Progress Reports in the non-competitive and competitive 
renewals.  The co-PIs will be responsible for contacting the NIH grant Program Officer in the event that any 
action resulting in temporary or permanent suspension of the study occurs.  The proposed research will adhere 
to all monitoring requirements imposed by 45 CFR Part 46. 
 
Plans for assuring data accuracy and protocol compliance.  Dr. Cox will supervise the study, including data 
management, data accuracy, and protocol compliance.  The study biostatistician and Study Manager will be 
the chief data managers and will adhere to established federal and institutional patient safety and protection 
guidelines.  To assure data accuracy, the Study Manager will review data system reports on a routine basis for 
the first 2 months followed by monthly thereafter.  These reports will show enrollment, missing data, and other 
values that are neither study ID- nor outcome-based.  The Study Manager will also be in charge of monitoring 
the safety system linked to weekly PHQ-9 surveys completed by active LIFT users—human oversight intended 

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to provide a redundant process given the importance of this safety feature.  Additionally, the Study Manager 
will process detailed routine reports to search for errors and generate basic reports for dissemination for 
regular staff meetings.   
 
Data safety monitoring board (DSMB). This RCT trial will be supervised by a single independent DSMB 
composed of professionals with significant experience in clinical trials, mind and body interventions, 
epidemiology, and biostatistics who are not directly involved in the study, its interpretation, or any study 
institution and have no active research relationship with a study team member—the same individuals who are 
overseeing the parent U01 factorial trial.   
 
The main responsibilities of the DSMB will be to (a) assess for the presence of potential harms and unintended 
consequences of the LIFT intervention, (b) ensure the validity and integrity of the data, and (c) make 
recommendations to the investigators and to the NIH about whether the study should be continued without 
modification, continued with modification, or terminated.  
 
The initial DSMB meeting will occur before the initiation of subject enrollment for the purpose of updating 
members on the study, ensuring agreement on the review process, establishing the review methodology and 
procedures, ensuring all conflicts of interest are disclosed (to be reviewed by NCCIH staff), reviewing the 
protocol, and codifying a written charter.  The NCCIH's Data Safety Monitoring Plan (DSMP) Template will be 
used to guide the drafting of the charter.  This document will specify procedures for protocol amendments, 
ensuring participant confidentiality and privacy, ensuring database protection, coordinating center 
responsibilities, creating adverse outcome definitions (adverse events, unanticipated problems, and serious 
adverse events), protocol for reporting and responding to adverse events while also maintaining subject 
confidentiality, justifying sample size, assessing accrual and compliance, halting and stopping rules (drafted 
with the assistance of the DSMB chair and the DSMB lead statistician), approving informed consent 
documents, and guidelines for quality control and quality assurance.  Before enrollment begins, the DSMB 
charter will be approved by both the DSMB and the NCCIH; additionally, ClinicalTrials.gov registration will be 
finalized as per the Milestone Plan shown in the Research Strategy document. 
 
The first DSMB data review will occur either after the first 50 participants have been enrolled—representing 
approximately 20% of randomization target—or enrollment has occurred for 6 months, whichever is observed 
first.  Thereafter, the DSMB will review cleaned data reports (provided by the Study Manager 2 weeks before 
the DSMB meeting) every 6 months during enrollment and follow up, and will prepare a report with any 
recommendations within 2 weeks following their review.  The specific study metrics that the DSMB will review 
at each meeting include:  enrollment rate, dropout rate, PHQ-9 scores, GAD-7 scores, PTSS scores, and 
Adverse Events.  The primary safety measures will be Adverse Events reports and PHQ-9 scores.  Other items 
reviewed by the DSMB at each meeting will include: (a) data quality, completeness, and timeliness; (b) 
performance of the individual sites; (c) adequacy of compliance with goals for recruitment and retention, 
including women and minorities; (d) protocol adherence; and (e) presence of factors that could adversely affect 
study outcome or compromise data confidentiality.  Study participants will be recovering from life-threatening 
illnesses managed in intensive care units which increase the likelihood of death over time in comparison to 
healthy individuals.  As such, any patient deaths and their cause during the follow up period will be recorded, 
discussed, and highly scrutinized.   
 
The study biostatistician, will oversee any DSMB statistical requests and interpretations.  During the review 
process, formal statistical tests may be performed under DSMB supervision if requested (e.g., examining the 
differences in Adverse Event or outcome rates between factor-based groups).  Additionally, the DSMB may 
request a formal statistical assessment if a suspicious increase in PHQ-9 score is observed in any factor-
based group.  If a specific factor group is found to have a statistically significant increase in PHQ-9 score, the 
DSMB scope of action may include recommendation for stopping the trial.  For differences in study dropout 
rates, appropriate changes to the protocol will be made by PI consensus after DSMB member input.  Any 

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protocol changes, as well as any adverse events, will also be immediately reported to the relevant site IRB, the 
Central Institutional Review Board (located at Duke University), as well as to the NIH Program Officer. 
 
Quality assurance and confidentiality:  We have a number of strategies to ensure the quality of the data.  First, 
the RedCAP electronic data entry system “forces” responses to key questionnaire items (e.g., primary 
outcomes surveys) before allowing progression through the particular interview’s template, thereby minimizing 
missing data.  For less critical items, delayed data entry is possible (though these data elements are non-
essential to primary aims analyses).  However, each time the clinical research coordinator logs into the secure 
data entry system, prompts appear on the welcome screen that show what data elements remain incomplete 
(as well as the time frame within which they must be entered) for all site participants.   
 
The study investigators will ensure the validity of the data system in a number of ways.  First, they will input 
data from 5-10 ‘dummy’ forms and cross-check it with the source data for accuracy, including the scoring of all 
study instruments.  Second, the investigators will examine electronic summary case report forms within the 
RedCAP system to ensure adequacy and accuracy of data collection as well as transcription to the database 
itself after enrollment of the first 5 participants.  Agreement will be reviewed and discrepancies will be 
discussed.   
 
Confidentiality will be safeguarded by a number of strategies.  Subjects will not be identified on any study 
reports.  University firewalls, multiple passwords, and encryption programs protect the security of the electronic 
data entry system, which will be housed on a highly secure Duke University server.  All personal computers are 
located in lockable offices and are accessible only by frequently changed passwords.  The server room is 
accessible only to designated University Systems Administrators.   
 
18. Privacy, Data Storage & Confidentiality 
18.a. BLUE CORAL 
Data will be collected from the Michigan FUNCTION group and entered into the HIPAA compliant BLUE 
CORAL REDCap database.  Only study personnel will have access to the REDCap database. Data 
from PETAL sites will remain in the PETAL central BLUE CORAL REDCap database overseen by the 
DCC at Massachusetts General Hospital. These data will include identifiers, in order to conduct post-
hospital telephone visits.  Identifiers will only be shared in accordance with all relevant human subjects’ 
protections.  
 
18.b. LIFT COVID RCT 
As noted above, data use agreements will be put in place to clarify data transferred from both the 
University of Michigan and the Massachusetts General Hospital and Duke University.  Non-BLUE 
CORAL data will be entered into a LIFT COVID database.  Data will be transmitted to Duke in CSV 
format from PETAL via secure, Duke University-approved, password protected, cloud systems (i.e., 
Box).  These data will be uploaded to a secure, password protected REDCap database housed on a 
Duke server. 
 
19.  DUHS IRB as Single IRB (sIRB) 
The Duke IRB will act as the single IRB for the LIFT COVID RCT and include Duke, Oregon Health & 
Sciences University, University of Colorado, and PETAL sites within its oversight.  We believe this is 
reasonable because of the low risk nature of the proposed trial, the good working relationships the Co-
PIs from each site have demonstrated in current and past work, and the expressed preferences of the 
NIH PETAL network.   
 
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