The Follow-up Automatically vs. As-Needed Comparison Trial
Phase: NA
Conditions: Pneumonia, Urinary Tract Infections, Soft Tissue Infections, Gastroenteritis
Sponsor: University of Utah

The Follow-up Automatically vs. As-Needed Comparison
(FAAN-C) Trial
Protocol Number 1.00
The Patient-Centered Outcomes Research Institute
Protocol Version 1.01
Version Date: June 4, 2024
Printing Date: June 12, 2024

Page 2 of 44
Protocol 1.00 (Coon)
Copyright © 2022. University of Utah School of Medicine on behalf of the Principal Investigator,
Eric Coon, M.D., M.S. All rights reserved.
This protocol is Protocol Number 1.00, and has been authored by Eric Coon, M.D., M.S., for
implementation with the investigators. This study is supported by IHS-2021C1-22388 awarded to
(PI:Eric Coon, M.D., M.S.) from the The Patient-Centered Outcomes Research Institute.
FAAN-C Protocol Version 1.01
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Protocol 1.00 (Coon)
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PROTOCOL TITLE:
The Follow-up Automatically vs. As-Needed Comparison (FAAN-C) Trial
Short Title: FAAN-C
Protocol Number: 1.00
Lead Investigator and Author:
Eric Coon, M.D., M.S.
Seattle Children’s Research Institute
Protocol Version: 1.01
Version Date: June 4, 2024
I confirm that I have read this protocol, I understand it, and I will conduct the study according to
the protocol. I will also work consistently with the ethical principles that have their origin in the
Declaration of Helsinki and will adhere to the Ethical and Regulatory Considerations as stated. I
confirm that if I or any of my staff are members of the Institutional Review Board, we will abstain
from voting on this protocol, its future renewals, and its future amendments.
Principal Investigator Name:
Principal Investigator Signature:
Date:
FAAN-C Protocol Version 1.01
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FAAN-C Protocol Version 1.01
Protocol Version Date: June 4, 2024

Contents
Contents
5
List of Tables
7
1
Study Summary
8
2
Background and Rationale
8
2.1
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
2.2
Rationale
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
3
Objectives and Outcomes
13
3.1
Primary Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
3.2
Secondary Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
3.3
Study Process Measure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
4
Study Outcomes
13
4.1
Selection of Outcomes
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
4.2
Primary Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
4.3
Secondary Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
4.4
Exploratory Outcomes
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
4.5
Safety Outcomes
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
4.6
Child health-related quality of life instrument
. . . . . . . . . . . . . . . . . . . .
17
5
Overall Study Design
17
6
Study Population
19
6.1
Treatment of Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
7
Treatment Assignment Procedures
20
7.1
Randomization
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
7.2
Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
8
Study Procedures
21
8.1
Study Schedule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
8.2
Screening and Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
8.3
The Parent Interview
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
8.4
Randomization Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
8.5
Chart Review
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
8.6
Outcome Measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
8.7
Strategies to Promote Retention . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
9
Data Analysis
24
9.1
Intent-to-Treat (ITT) population
. . . . . . . . . . . . . . . . . . . . . . . . . . .
24
9.2
Multiple Comparisons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
5

9.3
Analysis of the primary outcome . . . . . . . . . . . . . . . . . . . . . . . . . . .
25
9.4
Analysis of secondary outcomes
. . . . . . . . . . . . . . . . . . . . . . . . . . .
25
9.5
Analysis of exploratory outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
9.6
Heterogeneity of treatment effect (HTE) . . . . . . . . . . . . . . . . . . . . . . .
26
9.7
Instrumental variable analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
9.8
Missing Data
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
9.9
Sample Size and Power . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
10 Data Management
28
10.1 Study Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
10.1.1 Site Monitoring Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
10.1.2 Clinical Site Monitoring
. . . . . . . . . . . . . . . . . . . . . . . . . . .
28
10.1.3 Remote Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
10.2 Record Access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
11 Protection of Human Subjects
29
11.1 Institutional Review Board (IRB) Approval
. . . . . . . . . . . . . . . . . . . . .
29
11.2 Informed Consent Process
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
30
11.3 Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
30
11.4 Waivers Requested
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
11.5 Potential Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
11.6 Protections Against Potential Risks . . . . . . . . . . . . . . . . . . . . . . . . . .
31
11.7 Potential Benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
12 Data and Safety Monitoring Plan
32
12.1 Data Safety Monitoring Board (DSMB)
. . . . . . . . . . . . . . . . . . . . . . .
32
12.2 Safety Reporting
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
12.2.1 Definition of Medical Errors . . . . . . . . . . . . . . . . . . . . . . . . .
32
12.2.2 Definition of a Serious Adverse Event (SAE)
. . . . . . . . . . . . . . . .
33
12.2.3 Classification of an SAE (Relatedness, Severity, and Expectedness)
. . . .
33
12.2.4 Data Collection Procedures for SAE . . . . . . . . . . . . . . . . . . . . .
35
12.2.5 Unanticipated Problems (UP) . . . . . . . . . . . . . . . . . . . . . . . . .
35
12.2.6 Monitoring Serious Adverse Events
. . . . . . . . . . . . . . . . . . . . .
35
12.2.7 Follow-up of Serious Adverse Events
. . . . . . . . . . . . . . . . . . . .
36
13 Study Training
36
13.1 Study Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36
14 Regulatory Considerations
37
14.1 Health Insurance Portability and Accountability Act . . . . . . . . . . . . . . . . .
37
14.2 Inclusion of Women and Minorities . . . . . . . . . . . . . . . . . . . . . . . . . .
37
14.3 ClinicalTrials.gov Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . .
37
14.4 Retention of Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
37
14.5 Public Use Data Set . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
38
15 Bibliography
38
6

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List of Tables
1
Representative comments from family, hospitalist, and PCP focus groups . . . . . .
10
2
Results of the BeneFIT RCT . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
3
RCTs that suggest efforts to augment follow-up can potentially result in overtreatment 12
4
Selection of outcomes informed by focus groups . . . . . . . . . . . . . . . . . . .
14
5
Secondary, exploratory, and safety outcomes . . . . . . . . . . . . . . . . . . . . .
16
6
Study Population
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
7
Study Schedule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
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1
Study Summary
Title
The Follow-up Automatically vs. As-Needed
Comparison (FAAN-C) trial
Short Title
FAAN-C (pronounced “fancy”)
Design
FAAN-C is a multicenter randomized
controlled trial that will enroll 2,674 patients
across participating hospitals
Study Duration
5 years
Data Coordinating Center
University of Utah
Primary objectives
Compare the effectiveness of as-needed vs.
automatic post-hospitalization follow-up
Number of Subjects
2,674 patients
Eligibility Criteria
Children, hospitalized for pneumonia, skin and
soft tissue infection, acute gastroenteritis, or
urinary tract infection will be eligible for
enrollment.
Excluded: Children with a history of comorbid
disease that is both chronic and complex
Statistical Methodology
Analyses will be conducted in an
intention-to-treat (ITT) manner, in which all
randomized subjects are included and analyzed
according to their randomization assignment.
2
Background and Rationale
2.1
Background
Follow-up visits are common
A “follow-up visit” occurs when a medical provider instructs a
patient to schedule an additional medical visit for the purpose of re-evaluating the patient’s condition
in the future. Follow-up visits are utilized in nearly every clinical setting, including follow-up after
acute visits to primary care, urgent care, specialty care, the emergency department, or the hospital.
Nationally representative survey data from the 2018 Medical Expenditure Panel Survey demonstrate
that US children attend nearly 20 million follow-up visits annually, at a cost of $4.3 billion.1
Automatic post-hospitalization follow-up has intuitive appeal
The present proposal focuses on
one type of pediatric follow-up visit: the post-hospitalization follow-up visit. Most hospitalized
patients (>80%) are prescribed automatic post-hospitalization follow-up, meaning they are routinely
instructed to visit their primary care provider (PCP) shortly after hospital discharge, regardless of
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symptom improvement.2, 3 The majority of patients comply with these instructions and attend the
follow-up visit.3–5 The intuitive appeal of automatic follow-up is to provide an opportunity for PCPs
to connect with patients and their families to: verify that a patient is following an expected course,
adjust the treatment regimen if needed, provide additional reassurance about the patient’s illness,
and address any gaps in continuity of care (e.g., immunizations). Automatic follow-up is especially
intuitive for children with chronic and/or complex medical needs, who are at increased risk for
adverse events6, 7 and readmission.8–11 For this reason, discharge improvement interventions that
include automatic follow-up have focused on populations of children with chronic and/or complex
medical needs, such as children hospitalized for asthma,12 premature birth,13, 14 or major surgery.15
Automatic follow-up for previously healthy children recovering from common infections may
not be necessary
While the rationale for automatic follow-up is compelling for children who
have chronic and complex medical needs, most hospitalized children are previously healthy and
hospitalized for acute conditions from which complete recovery is expected.16, 17 Five of the top 10
reasons for pediatric hospitalization are acute infections, including: pneumonia, bronchiolitis, skin
and soft tissue infections, gastrointestinal infections, and urinary tract infections.18 Together, these
infections are responsible for over 500,000 pediatric hospitalizations each year in the US.18 After
hospital discharge, the vast majority of previously healthy children recover from these infections
within a matter of days and rarely experience an interim worsening of their illness (readmission rates
are <5%10). Given such a reassuring prognosis, the benefit of automatic follow-up for previously
healthy children recovering from common infections is unclear.
PRN follow-up is a patient and family-centered alternative to automatic follow-up
Patient
and family-centered care means that patient and family values guide all clinical decisions.19 Patients
and families whose preferences are incorporated into their plan of care make more value-congruent
choices20 and are more likely to follow the plan of care.21 A PRN (pro re nata, “as-needed”)
follow-up strategy is aligned with the principles of patient and family-centered care, encouraging
families to monitor their child’s symptoms after hospital discharge and schedule a visit if the child
does not improve or if new concerns arise. As such, PRN follow-up empowers families with greater
autonomy and allows them to consider their preferences and values when deciding whether or not
to pursue post-hospitalization follow-up. Taking this decision-making away from families runs
the risk of undermining their sense of self-efficacy—a patient’s or parent’s confidence to solve
self-identified problems.22 Despite being patient and family-centered, PRN follow-up is prescribed
to a minority of patients (10–15%) largely because of limited evidence.2, 3
Preliminary data
Families and medical providers struggle, not knowing which follow-up option
is best. To better understand the perspectives of end users of post-hospitalization follow-up, we
conducted three separate focus groups (Table 1), among: 1) parents of children who had been
hospitalized, 2) hospitalists (physicians who care for hospitalized children), and 3) PCPs. Focus
groups consisted of 6–8 participants each. Participants in each focus group came from at least
3 different FAAN-C institutions. Overall, families felt that their circumstances and the options
available to them were not adequately considered in post-hospitalization follow-up decision-making.
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Hospitalists expressed uncertainty about the available evidence to help guide their recommendations.
PCPs saw advantages to some follow-up visits, but worried that others were unnecessary. The
unifying theme for end-users was the need for better evidence to guide conversations and decision-
making around follow-up.
Table 1: Representative comments from family, hospitalist, and PCP focus groups
Focus group question
Representative participant comments
For families: What has been your
experience with follow-up care
instructions after your child’s
hospitalization?
“They tell you to go visit the doctor but they have no idea
if you have transportation, money for gas, money for
parking, help with child care”
“Whatever option they give you, you think that’s all there
is”
For hospitalists: Please describe
your decision-making for
post-hospitalization follow-up
recommendations to families.
“It’s a historical norm [automatic follow-up], that gives us
some reassurance, but it’s never been evidence tested”
“We normally do this [automatic follow-up], we always
have done it, but it isn’t backed in any confidence or any
evidence”
For PCPs: Please describe your
experience with
post-hospitalization follow-up
visits.
“For anxious families or families with unanswered
questions it’s been helpful”
“I feel bad when they’re in clinic and they look great, and I
say ok you’re better, sorry you have to pay a copay”
“Our schedules are really packed full and you hate to have
a family come in if they don’t really need to be there”
BeneFIT RCT demonstrates promise of PRN follow-up for one common pediatric infection. Our
team completed an RCT comparing PRN vs. automatic follow-up, called the Bronchiolitis Follow-up
Intervention Trial (BeneFIT).23 BeneFIT was a multicenter trial conducted across 4 hospitals. Bene-
FIT participants were 304 children hospitalized for a common infection called bronchiolitis. Results
from BeneFIT are presented in Table 2. Four-fold fewer families attended post-hospitalization
follow-up visits in the PRN group (19%) compared to the automatic group (81%). Both groups
otherwise had similar outcomes, including no significant differences in parent anxiety, symptom
duration, or readmission.
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Table 2: Results of the BeneFIT RCT
Outcome
PRN
N = 138
Automatic
N = 131
Absolute
Difference (95%
CI)
Attendance of a follow-up visit, n (%)
26 (19)
106 (81)
−63 (−53 to −72)
Parent anxiety score,a mean
3.9
4.2
−0.3 (−1.0 to 0.7)
Days to symptom resolution, mean
10
11
−1 (−3 to 1)
Readmission, n (%)
3 (2)
5 (4)
−2 (−6 to 2)
aPrimary outcome, scored by validated instrument;24 higher scores= greater anxiety
2.2
Rationale
The importance of examining post-hospitalization follow-up
Observational studies have
reached conflicting conclusions about post-hospitalization follow-up, with some studies finding
an association between automatic follow-up and decreased rates of hospital revisit25–31 and other
studies finding no association or increased rates of hospital revisit.32–37 BeneFIT remains one of
the only pediatric RCT to examine patient and family-centered outcomes for post-hospitalization
follow-up.23 Generalizations about post-hospitalization follow-up after BeneFIT are limited because
BeneFIT was not powered to detect differences in hospital readmission, and BeneFIT only enrolled
children with one specific type of infection, bronchiolitis. A systematic review of hospital discharge
interventions highlighted post-hospitalization follow-up as its first “Persistent Literature Gap.”38 A
national collaboration sponsored by the American Academy of Pediatrics’ Quality Improvement
Innovation Networks and the Section on Hospital Medicine concluded that certain quality measures,
including post-hospitalization follow-up, “require further study for feasibility, measurement reliabil-
ity and validity, and effectiveness in preventing harm.”39 Despite substantial gaps in the literature,
multiple quality metrics have been developed recently to promote automatic post-hospitalization
follow-up, including Pedi-BOOST, the Center of Excellence on Quality of Care Measures for
Children with Complex Needs, and the Pediatric Transition Experience Measure.40–43 Hospitals are
adopting these measures and promoting automatic post-hospitalization follow-up.4, 5
PRN follow-up has potential to improve delivery of care
High-value care makes efficient use
of resources and ensures that patients receive meaningful benefit.44 The “Triple Aim” in high-value
care is to simultaneously improve the patient experience of care, reduce the cost of care, and improve
the health of populations.45 PRN follow-up has the potential to achieve this status by decreasing the
amount of time that patients spend seeking medical care, decreasing patient costs, and decreasing
exposure to unnecessary medical tests and treatments.
1) Time and cost-savings. Clinic visits require an average of two hours of a family’s time and result
in out-of-pocket expenses and lost income.46 Out-of-pocket expenses include money for travel,
parking, co-pays, and child care. These burdens disproportionately affect racial/ethnic minority
and lower income families. For example, attendance of a clinic visit requires 30% more time
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for Hispanic and Non-Hispanic Black families compared to Non-Hispanic white families due to
increased travel and in-clinic time.47 Out-of-pocket healthcare expenditures relative to income
are >300% higher for families whose income is less than the Federal Poverty Level, compared to
high-income families.48 Lost income occurs when parents take time away from work to attend the
visit, which is particularly challenging for parents who may have already taken time away from
work during their child’s hospitalization. Lost income at the time of hospitalization is highest
for racial minority and single-parent households.49 PRN follow-up could mitigate these burdens
without compromising quality of care.
2) Decreased exposure to unnecessary medical tests and treatments. Seemingly benign medical
interventions have the potential to precipitate additional tests and interventions that are unnecessary,
costly, and potentially harmful.50–52 Four recent pediatric RCTs have compared PRN follow-up or
usual care to an intervention that augments follow-up (Table 3). In each RCT, augmented follow-up
resulted in more medical care, without otherwise improving patient outcomes. A pattern of increased
medical care that does not improve patient outcomes is concerning for overtreatment.53 For children
recovering as expected, avoidance of a post-hospitalization follow-up visit might reduce exposure
to overtreatment.
Table 3: RCTs that suggest efforts to augment follow-up can potentially result in overtreatment
RCT
Population
More
intensive
follow-up
group
Less
intensive
follow-up
group
Primary
Outcome
Potential Overtreatment
Auger et
al54
Hospitalized
children
(variety of
diagnoses)
Post-
discharge
nurse-led
home visit
No home
visit
30-day
reutilization
rate for urgent
health care
services
The 30-day reutilization rate
was higher in the augmented
follow-up group.
Auger et
al55
Hospitalized
children
(variety of
diagnoses)
A post-
discharge
telephone
call
No phone
call
30-day
reutilization
rate for urgent
health care
services
No significant difference,
but point estimate for the
30-day reutilization rate
higher in augmented
follow-up group.
Colaco et
al56
Children with
distal radius
buckle
fractures
Automatic
PCP
follow-up
PRN
follow-up
Parent report of
child’s physical
function 3
weeks after
injury
No difference in primary
outcome; more physician
visits, higher costs, and
more radiographs for
augmented follow-up.
Coon et
al23
(BeneFIT)
Hospitalized
children with
bronchiolitis
Automatic
PCP
follow-up
PRN
follow-up
Parental
anxiety 7 days
after discharge
No difference in primary
outcome; new prescriptions
at follow-up visits for
therapies discouraged by
national guidelines.57
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3
Objectives and Outcomes
3.1
Primary Objective
The primary objective of this study is to compare the effect of a recommendation for PRN vs. auto-
matic post-hospitalization follow-up on hospital readmission within 14 days of hospital discharge.
We hypothesize that a recommendation for PRN follow-up will be non-inferior to a recommendation
for automatic follow-up in terms of hospital readmission rates.
3.2
Secondary Objectives
Our secondary objectives are to determine the effect of a recommendation for PRN follow-up,
compared to a recommendation for automatic follow-up, on:
• medical interventions that a child receives after hospital discharge
• child health-related quality of life
3.3
Study Process Measure
The proportion of participants who attend a follow-up visit (in-person or via telehealth) within 7
days of hospital discharge will be reported but will not be categorized as a formal outcome. Rather,
the proportion of participants who attend a post-hospitalization follow-up visit will be a study
process measure. A prior trial demonstrated that randomization to a recommendation of PRN vs
automatic follow-up does result in a large difference in follow-up visit attendance.23 We hypothesize
that recommendations for PRN vs automatic follow-up in FAAN-C will similarly result in large
differences in follow-up visit attendance.
4
Study Outcomes
4.1
Selection of Outcomes
Selection of study outcomes was informed by the previously described focus groups involving
parents of hospitalized children, hospitalists, and PCPs. Illustrative quotes that influenced selection
of specific outcomes are presented in Table 4. Parents, PCPs, and hospitalists were clear that
hospital readmission should be the primary outcome.
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Table 4: Selection of outcomes informed by focus groups
Participant
Representative participant responses to a question asking which
outcomes would be important to study
Outcome added to
FAAN-C
Parent
“The impact on parents, their time away from work”
Parent time
Parent
“We’re all very invested in making sure things work out the best for
our kids, often at the expense of our own health. Anxiety would be
interesting to see because that plays into the situation and comes back
to impact our kids as well.”
Parent anxiety
Parent
“The one that really stands out to me is the number of times we have
to go back to the hospital after being sent home.”
Hospital readmission as the
primary outcome
PCPs
“I feel like I develop my relationship with my patients and families
through their well-child check-ups, not the sick or hospital follow-up
appointments.”
Well-child visits
PCPs
“I like to at least call my patients and parents after they are
discharged from the hospital to maintain that relationship.”
Telephone and electronic
communications with
medical providers
PCPs
“We worry that if kids don’t follow-up, are they going to get so bad
they need to be readmitted, so we hope that the follow-up prevents
readmission.”
Hospital readmission as the
primary outcome
Hospitalist
“I think it helps to strengthen the relationship between the PCP and
the family, so that they can see their PCP as not just the well doctor,
but the well and sick doctor.”
Usual place of medical care
Hospitalist
“I would look at health outcomes, readmission number one and
emergency department utilization.”
Hospital readmission as the
primary outcome; total
additional ambulatory
visits
4.2
Primary Outcome
The primary outcome is the proportion of participants who experience a hospital readmission within
14 days of their index hospital discharge. All causes of hospital readmission, even if seemingly
unrelated to the index infection, will be scored as a hospital readmission for the purpose of the
primary outcome. Hospital readmission will be measured primarily by parent report. On days 7,
14, and 30 after hospital discharge, parents will be surveyed and asked about hospital readmissions
since discharge. Parent report allows capture of readmissions that occur outside of a given hospital’s
electronic health record (EHR) system. However, parent report may be inaccurate for a proportion
of participants and will be missing for others. Parent report will be assumed inaccurate in two cases:
(1) a parent reports a readmission at a hospital whose records are available in the EHR, but there
is no readmission documented in the EHR. These cases will not be counted as readmissions. (2)
Cases in which a parent reports no readmission but there is a readmission documented in the EHR.
These cases will be counted as readmissions. When parent report is missing, imputation will be
utilized, as described in the missing data section.
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4.3
Secondary Outcomes
Medical interventions and child health-related quality of life are pre-specified as the main secondary
outcomes under consideration. Medical interventions are a main secondary outcome because
decreasing exposure to unnecessary medical tests and treatments is a core component of improving
healthcare value and a potential advantage of PRN follow-up. Medical interventions will be
measured by parent report. Child health-related quality of life is a main secondary outcome because
it is a patient-centered measure of how much a child’s health is impacting their usual activities or
routines. Child health-related quality of life will be measured by child report, unless the child is too
young to self-report or prefers parent report.
4.4
Exploratory Outcomes
Exploratory outcomes are listed in Table 5. If participants in the PRN follow-up group are able
to attend fewer post-hospitalization follow-up visits, the cost burden to parents, the child’s time
away from school or daycare, and parent time away from work and other responsibilities might be
lower. We hypothesize that a recommendation for PRN follow-up might result in greater telephone
and electronic communications between families and the child’s medical providers. It is possible
that a recommendation for PRN follow-up could serve as a missed opportunity to reconnect a child
and their primary care provider, resulting in small decreases in well-child visits, immunizations,
participants who report having a usual place of medical care, and medical interventions related to the
index infection. We hypothesize that the remainder of the exploratory outcomes (symptom duration,
parent self-efficacy, parent anxiety, and satisfaction with care) will be similar between participants
randomized to a recommendation for PRN follow-up compared to participants randomized to a
recommendation for automatic follow-up. All exploratory outcomes are measured by parent report,
from the time of hospital discharge until the specified time after discharge.
4.5
Safety Outcomes
Safety outcomes are also listed in Table 5. Safety outcomes were selected with the goal of capturing
adverse consequences (beyond hospital readmission, the primary outcome) that families might
experience as a result of a recommendation for PRN follow-up, compared to a recommendation
for automatic follow-up. A recommendation for PRN follow-up may result in those participants
having to attend a greater number of other types of ambulatory visits (e.g., emergency department
visits). The subset of non-primary care ambulatory visits will be measured because these visits
have the potential to be more burdensome for participants (i.e., larger co-pays and urgent, less
convenient visits), relative to a primary care visit. It is also possible that a recommendation for
PRN follow-up could result in greater exposure to medical errors after hospital discharge (e.g.,
medication problems, complications of care), since another medical provider may not connect with
the child and family shortly after hospital discharge. In addition to the primary outcome of all-cause
hospital readmission, an additional safety outcome will be hospital readmissions related to the index
infection. All safety outcomes are measured by parent report, from the time of hospital discharge
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until the specified time after discharge.
Table 5: Secondary, exploratory, and safety outcomes
Outcome
Definition
Expected
outcomes type
for analysisa
Secondary outcomes
Medical interventions
Proportion of participants who receive either a laboratory test, imaging
testb, or a new medication within 14 days of hospital discharge
Binary
Child health-related
quality of life
Mean health-related quality of life score 7 days after hospital
discharge, measured by the Impact on Activities and Routines
instrument
Normal
Exploratory outcomes
Cost burden
Mean total costs to parents (missed income and expenses) related to
the participant’s illness within 14 days of hospital discharge, measured
by the cost burden survey in Chang et al49
Binomial-
Gamma hurdle
Child time
Mean number of hours of school or daycare missed by the participant
within 14 days of hospital discharge as a result of their medical needs
Over-dispersed
Binomial
Parent time
Mean number of hours spent away from responsibilities (work or
non-work related) by parents within 14 days of hospital discharge as a
result of their child’s medical needs
Normal or
Gamma
Symptom duration
Proportion of participants who have completely recovered from their
infection at 7 days after hospital discharge
Binary
Total additional
ambulatory visits
Mean number of ambulatory visits (in-person or via telehealth) that a
participant attends, apart from the post-hospitalization follow-up visit,
within 30 days of hospital discharge; Ambulatory visits include clinic,
urgent care, and emergency department (not resulting in hospital
admission) visits.
Negative
Binomial
Non-primary care
ambulatory visits
Mean number of ambulatory visits (in-person or via telehealth) to
non-primary care providers, within 30 days of hospital discharge;
Non-primary care providers will include all providers outside of the
clinic that families identify as their primary care clinic.
Negative
Binomial
Parent self-efficacy
Mean self-efficacy score 7 days after hospital discharge, measured by
the PROMIS self-efficacy short form58
Normal
Parent anxiety
Mean anxiety score 7 days after hospital discharge, measured by the
PROMIS anxiety short form58
Normal or
Gamma
Satisfaction with care
Proportion of participants who report agreeing or strongly agreeing
with the statement, “I am satisfied with the medical care my child has
received since hospital discharge,” 7 days after hospital discharge
Binary
Telephone and
electronic
communications with
medical providers
Mean number of telephone and electronic (excluding telehealth visits)
communications with a medical provider within 14 days of hospital
discharge
Negative
Binomial
Well-child visits
Proportion of participants who attend a well-child visit within 6
months of hospital discharge
Binary
Immunizations
Proportion of participants who receive an immunization within 6
months of hospital discharge
Binary
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Usual place of medical
care
Proportion of participants who report having a usual place of medical
care 6 months after hospital discharge
Binary
Medical interventions
related to the index
infection
Proportion of participants who receive either a laboratory test,
imagingb test, or a new medication related to the index infection
within 14 days of hospital discharge
Binary
Safety outcomes
Medical errors
Proportion of parents who report that their child experienced a medical
error within 14 days of hospital discharge, measured by the Family
Safety Interview59
Binary
Hospital readmissions
related to the index
infection
Proportion of participants who experience a hospital readmission
related to the index infection within 14 days of hospital discharge
Binary
aOutcome type designations, particular as normal or gamma, are preliminary and may be updated based on the
observed skewness in the outcome variables.
bUrogenital imaging for urinary tract infections will be excluded from this measure because urogenital imaging is
often recommended by guidelines and the potential benefits of such imaging have a longer time horizon than the
present study.
4.6
Child health-related quality of life instrument
All instruments will be scored as described in the referenced publications. The Impact on Activities
and Routines Instrument, used to measure child health-related quality of life, has not been published
yet. For this reason, we describe this instrument and its scoring here. The Impact on Activities and
Routines Instrument has the option of using a child-reported question or a parent-reported question.
The child-reported question will be utilized, unless the participant is too young to self-report or
prefers parent report. The child reported question is: In the past 7 days, how much did the medical
concern that led to your hospitalization impact your usual activities or routines (e.g., go to school,
play, eat, sleep)? The parent-reported questions that will be used, if necessary, is: In the past 7
days, how much did the medical concern that led to your child’s hospitalization impact their usual
activities or routines (e.g., go to school, play, eat, sleep)? Answer choices to both questions are: 1,
Not at all | 2, Slightly | 3, Moderately | 4, Quite a lot | 5, Extremely. Mean score responses will be
used in analyses.
5
Overall Study Design
FAAN-C is a multicenter RCT that will enroll 2,674 patients across approximately 10 hospitals,
including children’s and community hospitals. Inclusion of community hospitals is a priority because
community hospitals care for the majority of hospitalized children in the US17 but are historically
underrepresented in research.60, 61 FAAN-C is powered for non-inferiority of a recommendation
for PRN follow-up compared to a recommendation for automatic follow-up, with 14-day all-cause
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hospital readmission as the primary outcome. Non-inferiority trials test the hypothesis that one
intervention is not worse than a comparator with respect to the primary outcome. This design is
useful when evaluating an intervention that is more efficient, less prone to adverse events, and/or
less costly than the accepted comparator.62 If non-inferiority is demonstrated, patients can benefit
from a simpler, safer alternative intervention. In the case of FAAN-C, there are clear advantages to
PRN follow-up over automatic follow-up. Namely, a recommendation for PRN follow-up affords
families the convenience of not necessarily having to attend another medical appointment, which
means decreased costs and decreased time away from work and school. As such, FAAN-C fits a
non-inferiority trial design. If PRN follow-up is shown to be non-inferior to automatic follow-up
for the primary outcome (and safety outcomes are similar), the convenience and cost advantages of
PRN follow-up are manifest enough that PRN follow-up would generally be preferred to automatic
follow-up.
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6
Study Population
Table 6 details the inclusion and exclusion criteria for participants in FAAN-C. Eligible participants
must meet all inclusion criteria and none of the exclusion criteria.
Table 6: Study Population
Inclusion Criteria
Exclusion Criteria
Pneumonia
– Age <18 years
– Hospitalized
(including
observation visits)
– Parent speaks
English or
Spanish
– Attending
diagnosis of
pneumonia as the
principal disease
that led to hospital
admission
– Presence of a
comorbid disease that is
both chronic and
complex*
– principal disease
required surgical
intervention (beyond
superficial incision and
drainage)
– Received a chest
tube
Urinary Tract
Infection
– Attending
diagnosis of
urinary tract
infection as the
principal disease
that led to hospital
admission
– Immunodeficiency
(innate or receiving a
long-term
immunosuppressive
medication)
– A well-child check-up
or post-hospitalization
follow-up visit is
already scheduled
within 7 days of hospital
discharge
– History of
neurogenic bladder or
urologic surgery
(beyond circumcision)
– Renal imaging
anticipated within 7
days of hospital
discharge
– Complicated by a
renal abscess
Skin and soft
tissue infection
– Attending
diagnosis of skin
and soft tissue
infection as the
principal disease
that led to hospital
admission
– Parent or participant
strongly prefers PRN or
automatic follow-up
– A medical provider
feels strongly that a
post-hospitalization
follow-up visit is
needed within 7 days of
hospital discharge
– Chronic wound
– Postoperative
infection
– Predisposition to
poor wound healing
– Discharging with a
drain in place
– Complicated by
necrotizing fasciitis or
toxic shock syndrome
Acute
Gastroenteritis
– Attending
diagnosis of acute
gastroenteritis as
the principal
disease that led to
hospital
admission
– Sibling concurrently
hospitalized
– Unable to identify a
clinic where the
participant would
receive any needed
post-hospitalization
follow-up
– Complicated by
hemolytic uremic
syndrome
*Definition of comorbid disease that is both chronic and complex: Any disease that can be reasonably expected to
last at least 12 months (unless death intervenes) and to involve either several different organ systems or 1 organ
system severely enough to require specialty pediatric care and probably some period of hospitalization in a tertiary
care center63
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6.1
Treatment of Subjects
At the time of hospital discharge, families will be randomly assigned to either PRN or automatic
follow-up recommendations as described below:
PRN follow-up: “You do not need to schedule a follow-up visit with your child’s regular doctor
today. If your child’s illness continues to improve, you do not need to have a visit with your child’s
regular doctor within the next 7 days. If your child’s illness does not seem to be getting better or you
develop any new concerns, we recommend that you contact your child’s regular doctor to discuss
whether a follow-up visit might be necessary.”
Automatic follow-up: “Please schedule a follow-up visit with your child’s regular doctor before
leaving the hospital. Please schedule the visit to occur within the next 7 days and plan to attend the
visit even if your child’s illness is getting better.”
The automatic follow-up instructions are aligned with proposed quality metrics40 and previous
studies of automatic follow-up.25, 26, 28, 32, 34 Both the PRN and automatic follow-up instructions
were utilized successfully for our prior trial, BeneFIT.23
Pragmatic features of comparators. Pragmatic features that will make findings from FAAN-C more
generalizable and quickly scalable include the following: 1) Follow-up visits, whether automatic
or deemed necessary in the PRN group, can be conducted either in-person or via telehealth. The
decision about whether a visit should occur in person or via telehealth will be at the discretion of
families and their medical providers. 2) Beyond randomization to either PRN or automatic post-
hospitalization follow-up recommendations, FAAN-C is not otherwise prescriptive for a participant’s
medical care. Hospitalists have complete autonomy about the patient’s care while hospitalized, and
PCPs have complete autonomy for the patient’s care after hospitalization. 3) Beyond embedding
follow-up instructions in the electronic health record, the discharge process is otherwise preserved
according to each hospital’s usual procedures.
7
Treatment Assignment Procedures
7.1
Randomization
Randomization will be performed using randomly permuted blocks of random sizes, stratified by
the four types of infection and hospital site. Children will be assigned in a 1:1 ratio to receive
a recommendation for either PRN or automatic post-hospitalization follow-up. Randomization
sequence generation will be performed by study investigators who are not involved in the interven-
tion assignment of enrolled participants. Allocation concealment will be maintained by a central,
automated computer platform (REDCap).
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7.2
Blinding
Owing to the nature of the comparators, blinding of participants and their medical providers is
not possible. However, outcomes that require adjudication will be adjudicated by persons blinded
to the subject’s randomized group. Outcomes requiring adjudication in FAAN-C are the safety
outcomes (hospital readmissions related to the index infection and medical errors). Specifically, a
clinician will determine if the readmission was related to the index infection and a separate clinician
will score parent-reported medical errors in terms of severity (as described in the Safety Reporting
section of this protocol). The clinicians performing adjudication of these outcomes will be blinded
to the subject’s randomized group.
8
Study Procedures
8.1
Study Schedule
A schedule of study events for each participant is outlined in Table 7. “While hospitalized” events
will occur between the time of hospital admission and the time of hospital discharge.
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Table 7: Study Schedule
While hos-
pitalized
After hospital discharge
Day 7
Day 14
Day 30
Day 180
Screening
/
Informed consent
/
Parent interview
/
Randomization
/
Notify family, PCP, and inpatient team of
assignment
/
Chart review
/
Process measure
Completion of a post-hospitalization follow-up
✕
Outcomes
All-cause hospital readmissions
⃝
✕
⃝
Medical interventions
⃝
✕
⃝
Child health-related quality of life
⃝
✕
⃝
⃝
Cost burden
⃝
✕
⃝
Child time
⃝
✕
⃝
Parent time
⃝
✕
⃝
Symptom duration
⃝
✕
⃝
⃝
Total additional ambulatory visits
⃝
⃝
✕
Non-primary care ambulatory visits
⃝
⃝
✕
Parent self-efficacy
⃝
✕
⃝
⃝
Parent anxiety
⃝
✕
⃝
Satisfaction with care
⃝
✕
Telephone or electronic communications with
medical providers
⃝
✕
⃝
Well-child visits
⃝
✕
Immunizations
⃝
✕
Usual place of medical care
⃝
✕
Medical interventions related to the index
infection
⃝
✕
⃝
Medical errors
⃝
✕
⃝
Hospital readmissions related to the index
infection
⃝
✕
⃝
/ = task performed at the specified timepoint
⃝= measured at the specified timepoint
✕= measured at the specified timepoint and this is the timepoint used for primary analyses
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8.2
Screening and Informed Consent
Study staff will regularly review the list of hospitalized patients at their site. Study staff will
verify eligibility by a combination of reviewing the subject’s medical record and discussion with
the inpatient team caring for the patient, as necessary. After study eligibility has been verified,
study staff will approach the parents of the eligible child for consent (and assent from the child, as
appropriate). Parents who consent to study participation will then be asked to participate in the
parent interview. Within REDCap, a record will be kept of all screened but not enrolled participants.
Reasons for not enrolling will be recorded.
8.3
The Parent Interview
The parent interview will obtain sociodemographic data (e.g., race, ethnicity, financial hardship)
about the child and the child’s parents. Baseline measurements of the outcomes that are measured
during hospitalization will also be measured during the parent interview. Screening, consent, and
the parent interview will occur before randomization.
8.4
Randomization Process
Randomization will occur when study staff learn that hospital discharge for the study participant
is likely to be that day and/or discharge orders have been placed. Prior to randomization, study
staff will complete an enrollment checklist in REDCap. The enrollment checklist will verify
that all necessary pre-randomization items have been completed. When the enrollment checklist
is complete, REDCap will supply the study staff with the patient’s randomization assignment.
Study staff will notify the patient and their parents of their randomization assignment and their
recommended follow-up strategy (PRN or automatic follow-up). Study staff will also communicate
the participant’s randomization assignment to the participant’s inpatient medical team and PCP.
8.5
Chart Review
Study staff will perform chart review. We will collect data elements related to each child’s past
medical history (e.g., comorbidities), as well as the complexity and severity of their acute infection
while hospitalized (e.g., presence of bacteremia, need for intensive care). Chart reviewers will
also record readmissions. For each readmission, data elements for the severity and complexity
of the illness(es) for which the participant was readmitted will be collected. Chart review can
begin anytime after a participant is discharged from the hospital but cannot be completed until the
participant is at least 30 days out from discharge.
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8.6
Outcome Measurement
Outcomes will be measured according to the timing in Table 7. “While hospitalized” outcomes
will be measured prior to randomization. “After hospital discharge” outcomes will be measured by
surveying parents on days 7, 14, 30, and 180, as specified. An additional 4 days will be permitted
for the collection of data on the 7, 14, and 30 day timepoints and ± 7 days for the day 180 timepoint.
For example, day 7 outcomes can be collected between day 7 and day 11. These intervals allow for
holidays, weekends, and other reasons for parent unavailability that may preclude contact on the
exact day.
8.7
Strategies to Promote Retention
We will utilize the following strategies to promote study retention: 1) Participating families will
receive a $20 gift card at enrollment and an additional $20 gift card for answering each subsequent
study-related survey ($100 in total); 2) We will use multiple methods of contact for parents, including
home and cell phone numbers and email addresses. 3) Parents will provide days and times when a
phone call is most convenient.
9
Data Analysis
9.1
Intent-to-Treat (ITT) population
Analyses will be conducted in an intention-to-treat (ITT) manner, in which all randomized subjects
are included and analyzed according to their randomization assignment.64 Subjects who withdraw
or get removed from the study will be included in the ITT population. The ITT population will be
used for the primary analysis as well as for safety analyses.
9.2
Multiple Comparisons
The studywise Type-1 error will be controlled by designating a single primary outcome, defined
as all-cause hospital readmission within 14 days of discharge. The primary analysis will test
the noninferiority of a recommendation for PRN follow-up compared to a recommendation for
automatic follow-up on hospital readmission within 14 days of hospital discharge using a 1-sided
α-level of 0.05.
The trial design also includes two secondary outcomes, the occurrence of a medical intervention, and
health-related child quality of life as measured by the Impact on Activities and Routines instrument.
We will evaluate both of these secondary outcomes for treatment efficacy using 2-sided hypothesis
tests. We will use the Bonferroni-Holm procedure to assure a studywise α-level of 0.05 for the two
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secondary outcomes considered jointly. In the Bonferroni-Holm procedure, we will first compute
2-sided p-values for both secondary outcomes. If the smaller of the two p-values is < 0.025, the
treatment comparison for that outcome will be declared statistically significant, and the larger
p-value will be compared to 0.05 to determine if the other comparison is also statistically significant.
If the smallest of the two p-values is ≥0.025, then the treatment comparisons for both secondary
outcomes will be regarded as not statistically significant.
To avoid reducing statistical power, comparisons of safety outcomes will be performed using 2-sided
α-levels of 0.05 for each safety outcome on a comparisonwise basis, without adjustment for multiple
comparisons.
All other outcomes are exploratory.
9.3
Analysis of the primary outcome
The risk of all-cause hospital readmission within 14 days of hospital discharge will be compared
between the groups who receive a recommendation for PRN vs. automatic follow-up by applying
maximum likelihood estimation under a log binomial generalized linear model with indicator
variables for randomized treatment, the four infection types, and hospital site included in the models
as predictor variables. The primary results will be expressed as a risk difference with a 95% upper
confidence bound. In the event that log binomial model fails to converge, the risk ratio with the
95% upper confidence bound will be estimated by applying logistic regression (with a logistic link
function) and using the marginal means approach to estimate the risk of the outcome first setting the
treatment variable to “automatic” for all patients and then setting the treatment variable to “PRN”
for all patients, and performing statistical inference using bootstrap resampling.
The test of noninferiority will be performed by constructing a 95% upper confidence bound for the
difference in risk of a hospital readmission within 14 days under the as-needed treatment group vs.
automatic follow-up group. Noninferiority will be inferred if this confidence bound excludes the
noninferiority margin of 2.5%.
9.4
Analysis of secondary outcomes
Similarly to the primary outcome, the probability of a medical intervention within 14 days of
hospital discharge will be compared between the groups who receive a recommendation for PRN vs
automatic follow-up by applying maximum likelihood estimation under a log binomial generalized
linear model with indicator variables for randomized treatment, the four infection types, and hospital
site included in the models as predictor variables. The estimated treatment effect will be expressed
as a risk difference with a 2-sided 95% confidence interval. In the event that log binomial model
fails to converge, the risk ratio with 95% confidence intervals will be estimated by applying logistic
regression (with a logistic link function) and using the marginal means approach to estimate the risk
of the outcome first setting the treatment variable to “automatic” for all patients and then setting the
treatment variable to “PRN” for all patients, and performing statistical inference using bootstrap
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resampling.
The mean health-related quality of life score 7 days after hospital discharge, measured by the
Impact on Activities and Routines instrument, will be compared between the groups who receive a
recommendation for PRN vs automatic follow-up by applying an analysis of covariance, with the
baseline quality of life score, the four infection types, and hospital site included in the model as
covariates. The estimated treatment effect will be expressed as a mean difference in the health-related
quality of life score between the randomized groups with a 2-sided 95% confidence interval.
9.5
Analysis of exploratory outcomes
Generalized linear models with normal, gamma or lognormal, binary, binomial, and negative
binomial outcome models will be used in ITT analyses to compare symmetric numeric, positively
skewed numeric, dichotomous, count outcome assessed a designated number of times, and count
outcomes without a fixed number of assessments, respectively, between the PRN and automatic
follow-up recommendation groups.65, 66 Hospital site and type of infection will again be included
as covariates. Effects will be expressed as a difference in means between the PRN and automatic
follow-up recommendation groups for normal outcomes, as a ratio of means for gamma and log-
normal continuous outcomes, as risk ratios for binary outcomes, and as rate ratios for binomial
and negative binomial outcomes. As for the primary outcome, if the log binomial model fails to
converge, relative risks for binary outcomes will be analyzed by applying logistic regression with
the marginal means approach and bootstrap resampling. Analyses using the binomial outcome
model will account for overdispersion. Several numeric outcomes will be evaluated longitudinally.
For these outcomes, we will adjust for the baseline level of the outcome (measured on day 0),
which improves statistical power by framing the analysis as an analysis of covariates (ANCOVA),
as is recommended in randomized trials. Log-rank tests with stratification of the baseline hazard
by hospital site and type of infection will compare time-to-event outcomes between groups. The
log-rank test will be used to compare child symptom duration between randomized groups, with a
hazard ratio estimating using Cox regression.
9.6
Heterogeneity of treatment effect (HTE)
HTE analyses will be hypothesis-generating, with the goal of identifying populations of patients for
whom a recommendation for PRN follow-up is particularly effective. HTE analyses will evaluate
the consistency of treatment effects on the primary outcome across the four types of infection, as
well as patient race, ethnicity, finacial and social hardship, and use of telehealth for follow-up. The
log-binomial generalized linear model for the primary outcome will be repeated for each subgroup.
In addition, for each subgroup factor the log-binomial model for the full cohort will be extended
by including interaction terms between the randomized treatment and the subgroup factor. The
results of these subgroup analyses will be displayed by a forest plot containing risk ratios with 95%
confidence intervals for each subgroup, with interaction p-values displayed on the plot.
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9.7
Instrumental variable analysis
We will supplement the ITT analysis with an instrumental variable analysis, which is a type of
per-protocol analysis and is a recommended component of non-inferiority trials.67, 68 We will use
randomization as the instrument to approximate the average causal effect on patient outcomes
of actually attending a post-hospitalization follow-up visit. While the ITT analysis evaluates the
average effect of assigning subjects to a recommendation for PRN vs automatic follow-up in the
full cohort, an instrumental variable analysis estimates the average effect of actually receiving
a follow-up visit among patients who would attend the visit if assigned to an automatic follow-
up recommendation, but not if assigned to a PRN follow-up recommendation. The instrumental
variable analysis depends on two key assumptions: 1) the randomized treatment influences outcomes
only through the effect of treatment assignment on the occurrence or nonoccurrence of a follow-up
visit, and 2) randomization to a PRN follow-up recommendation does not cause any subjects to
attend a follow-up visit when they would not have done so if randomized to an automatic follow-up
recommendation.69
9.8
Missing Data
We will use multiple imputation based on fully sequential imputation with predictive mean matching
to impute missing data.70 Multiple imputation will be particularly useful because we expect to have
strong auxiliary variables—that is, variables that are highly correlated with study outcomes and
risk of missingness. Auxiliary variables we will utilize include patient demographic factors (e.g.,
race, ethnicity) measures of illness severity (e.g., length of stay, disease-specific characteristics),
and hospital readmission documented in the electronic medical record.
9.9
Sample Size and Power
The RCT will be powered for non-inferiority of a recommendation for PRN follow-up compared
to automatic follow-up for the primary outcome, 14-day all-cause hospital readmission. In 2019,
the mean 14-day all-cause readmission rate across FAAN-C sites among patients who would meet
inclusion criteria for FAAN-C was 3.5% (extracted from the Pediatric Health Information Systems
database on April 29, 2020). Given that automatic post-hospitalization follow-up is recommended
to the majority of hospitalized children, we used 3.5% as the estimated readmission rate for the
automatic post-hospitalization follow-up group. We set the non-inferiority margin at 2.5% because
hospitalists and PCPs reported in focus groups that they would consider a recommendation for
PRN follow-up to be inferior to a recommendation for automatic follow-up if the PRN follow-up
recommendation resulted in a more than 2–3% absolute increase in hospital readmissions. At a
margin of 2.5%, the parents of 40 children would need to be instructed to have automatic follow-up
visits before 1 hospital readmission would be prevented (that is, the number needed to treat71 =40).
If ≥40 parents would need to be instructed to have automatic follow-up to prevent a hospital
readmission, we will conclude that a recommendation for PRN follow-up is non-inferior to a
recommendation for automatic follow-up. We assume that the primary outcome will be available
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for at least 85% of subjects (15% attrition). Under these assumptions, a total sample size of
2,674 patients (1,337 patients in each group) will provide 90% power with 1-sided α=0.025 to
demonstrate non-inferiority of a recommendation for PRN follow-up. We defined the non-inferiority
margin without adjusting for non-compliance for two main reasons. First, patients randomized to a
recommendation for PRN follow-up are compliant whether or not they choose to attend a follow-up
visit. Secondly, the assumed readmission rate for the automatic follow-up group (3.5%) is derived
from a sample from which non-compliance occurred. Non-compliance is expected to be greater
outside of a trial setting, which preserves our conservative power estimate.
10
Data Management
10.1
Study Monitoring
The investigators recognize the importance of ensuring data of excellent quality. Study monitoring
is critical to this process. Monitoring has been a very effective tool for maintaining data quality in
previous studies, and we will utilize this process to ensure excellent quality data in the proposed
study. The Data Coordinating Center utilizes risk-based methodology to identify and correct
problems that may arise at sites. The risk-based approach to monitoring focuses on oversight
activities and preventing or mitigating key risks to data quality, as well as to processes critical to
human subject protection and integrity of the trial or study.
Study monitors must be provided with appropriate access to study materials and the medical records
for study subjects. If the medical records are in electronic form, the clinical investigator or an
authorized individual must provide any assistance necessary to facilitate the study monitor’s review
of data in the electronic medical record.
10.1.1
Site Monitoring Plan
A supplemental study-specific risk-based monitoring plan, separate from the protocol will be
completed which outlines specific criteria for monitoring. This plan may include the number of
planned site visits, criteria for focused visits, additional visits or remote monitoring, a plan for chart
review and a follow-up plan for non-compliant sites. The monitoring plan also describes the type of
monitoring that will take place (e.g., sample of all subjects within a site; key data or all data), the
schedule of visits, how they are reported and a time frame to resolve any issues found.
10.1.2
Clinical Site Monitoring
Site monitoring visits may be performed during the study period to ensure regulatory compliance,
patient safety, and to monitor the quality of data collected. Essential document binders, regulatory
documents and data collection forms may be reviewed. The site monitor will provide each site with
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a written report, and sites will be required to follow-up on any deficiencies. The site initiation may
take place as group training made up of site investigators and research assistants.
10.1.3
Remote Monitoring
The Data Coordinating Center may supplement on-site monitoring with remote monitoring activities.
Remote monitoring involves detailed review of the data entered by each site and consultations with
each site investigator and/or research coordinator to review safety and data quality. This may require
uploading copies of medical records, patient study files, regulatory documentation, or other source
documents for the monitor to review. Alternatively, other methods, such as remotely viewing source
documentation, may be utilized. This helps assure protocol compliance and accurate data collection.
The Data Coordinating Center may conduct more remote monitoring activities early in the trial
to assure protocol compliance and identify any training issues that may exist. Remote monitoring
documents will be retained in accordance with federal requirements. Safety of subjects will be
monitored and ensured in accordance with the Data and Safety Monitoring Board (DSMB) plan.
10.2
Record Access
The medical record and study files (including informed consent, permission, and assent documents)
must be made available to authorized representatives of the Data Coordinating Center, upon request,
for source verification of study documentation. In addition, medical information and data generated
by this study must be available for inspection upon request by representatives (when applicable) of
the, NIH, other Federal funders or study sponsors, and the Institutional Review Board (IRB) for
each study site.
11
Protection of Human Subjects
11.1
Institutional Review Board (IRB) Approval
The Institutional Review Board (IRB) at the University of Utah will serve as the single IRB. The
Utah IRB has extensive experience with single IRB implementation due to our participation in the
NCATS funded Trial Innovation Center, which has implemented over 35 SIRB studies, several with
EFIC.
In addition to SIRB activities, each institution has Human Research Protection activities that will
be completed prior to site activation. These include conflict of interest, assuring competence of
investigators, impact on hospital services, etc., and are individualized to each site.
The Data Coordinating Center will track IRB approval status at all participating centers and will
not permit subject enrollment without documentation of initial IRB approval and local review
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sign-off. The Data Coordinating Center will also track the maintenance of that approval throughout
subsequent years of the project.
11.2
Informed Consent Process
SIRB procedures should be well understood by all research staff and clearly documented in the
Essential Documents Binder or eBinder.
GCP Reminder (Informed consent advice from OHRP): Informed Consent is a process, not a form.
Information must be presented to enable the person to voluntarily decide whether or not to participate
as a research subject. It is a fundamental mechanism that ensures respect for persons through
provision of thoughtful consent for a voluntary act. The procedures used in obtaining informed
consent should be designed to educate the subject population in terms that they can understand.
Think of the document primarily as a teaching tool not as a legal instrument. http://www.hhs.
gov/ohrp/regulations-and-policy/guidance/informed-consent/index.html
The informed consent process can be a collaborative effort between research staff, the site PI and
Co-PIs, and clinicians. However, if the site PI/Co-PI are unavailable research staff may introduce
the study and proceed through the informed consent process. A PI or CO-PI should always be
available by phone to the research staff to answer any additional questions the family may have as
needed in the rare case that the research staff is unable to answer specific questions.
11.3
Informed Consent
The informed consent/parental permission document must be approved by the SIRB and local
HRPP prior to conducting any research activities. The informed consent/parental permission must
be signed before any study procedures begin. ALL subjects participating must have a signed and
dated consent form/parental permission form as part of the patient study file. An electronic or
paper copy of the signed and dated consent form/parental permission form will be provided to the
patient. At some institutions the form must also be signed and dated by the person obtaining the
consent/parental permission.
Parental Permission
Subjects who are eligible for this study are under 18 years of age, and written permission from
parents or legal guardians will be required for participation. After determining that a subject
is eligible, the site investigator or designee will approach the parent or legal guardian to offer
participation for their child in the study. The parent or legal guardian will be informed about the
objectives of the study and the potential risks and benefits of participation. Subject will only be
enrolled if their parent or guardian provides permission for their child to participate.
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Child Assent
Children who are capable of giving assent and who are alert and competent, will be asked, following
an age-appropriate discussion of risks and benefits, to give assent to the study or further study
procedures. Assent will be waived if the child is too young, has a severely reduced mental age,
decreased level of consciousness, psychological problems, or other legitimate reasons as judged by
the Institutional Review Board.
Subject Consent
If a subject attains the age of 18 years during the study period, informed consent is required. Subjects
who are capable of giving consent and who are alert and competent, will be asked, following an
appropriate discussion of risks and benefits, to give consent to the study. For those with diminished
mental capacity, a Legal Authorized Representative will be used.
11.4
Waivers Requested
Waiver of Authorization
A waiver of authorization is requested in order to be able to pre-screen/establish eligibility for
subject prior to approaching, consenting, and enrolling a subject.
Waiver of Documentation of Informed Consent
The waiver is requested for subjects who reach the age of majority (18 years), after randomization.
11.5
Potential Risks
Loss of confidentiality of the subject is a potential risk of the study; however, safeguards are in
place to protect against this.
11.6
Protections Against Potential Risks
To protect against a loss of confidentiality, the information gathered for this study will be coded
with a special study number. A child’s or parent’s name and information that could identify them
will be stored securely at the site where they were enrolled or in the study database.
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11.7
Potential Benefits
There are no likely benefits anticipated from participation in this study; however, there is potential
benefit to others because of the knowledge that may be gained from this research.
12
Data and Safety Monitoring Plan
12.1
Data Safety Monitoring Board (DSMB)
The study will have a Data Safety Monitoring Board (DSMB). The DSMB will have a charter,
will approve the protocol prior to implementation, and will review interim analyses as applicable.
The purpose of the DSMB is to advise the sponsors and Principal Investigator(s) regarding the
continuing safety of study subjects and the continuing validity and scientific merit of the study. The
DSMB is responsible for monitoring accrual of study subjects, adherence to the study protocol,
assessments of data quality, performance of individual site, review of serious adverse events and
other subject safety issues. There will be no formal stopping rules for efficacy or futility.
12.2
Safety Reporting
Hospital readmissions and medical errors are outcomes being collected for this study. These data
constitute safety events and will provide an adequate method of assuring subject safety in the study.
Safety events will be reported to the DSMB at regular meetings in a standard fashion and will be
reviewed regularly at the DCC.
12.2.1
Definition of Medical Errors
Medical Errors
Medical errors will be collected as described in the outcomes section above.
Examples of medical errors captured within this outcome include parent-reported medication
problems, miscommunications, diagnostic mistakes, delays in care, complications of care, and
equipment problems. Medical errors will be categorized into levels of harm using the National
Coordinating Council for Medication Error Reporting and Prevention Index for Categorizing
Medication Errors Algorithm.72 This algorithm categorizes harms on a continuum from A–I, with
the extremes being the absence of a true error (harm level A) and an error that resulted in patient
death (harm level I). Harm levels F (initial or prolonged hospitalization required), G (life-sustaining
intervention required but harm was not permanent), H (life-sustaining intervention required and
harm was permanent), and I (death resulted) meet the definition of serious adverse events outlined
below and will be reported as described below.
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12.2.2
Definition of a Serious Adverse Event (SAE)
Serious Adverse Event (SAE):
A serious adverse event (SAE) for this population is an error or
event that:
• results in death; or
• is life-threatening (the patient was, in the view of the site investigator, in immediate danger of
death from the event as it occurred); or
• prolongs an existing hospitalization; or
• results in persistent or significant disability or incapacity; or
• results in congenital anomaly/birth defect; or
• any other event that, based upon appropriate medical judgment, may jeopardize the subject’s
health and may require medical or surgical intervention to prevent one of the other outcomes
listed in this definition.
Hospital readmission will already be captured as the primary outcome so these will not be reported
as SAEs unless the PI determines this is necessary. SAEs will be captured between randomization
and 14 days after hospital discharge.
12.2.3
Classification of an SAE (Relatedness, Severity, and Expectedness)
Relatedness:
The suspected relationship between study interventions and any SAE will be
determined by the site investigator using the criteria below. Relatedness must be assessed by an
investigator and may not be assessed by a research coordinator.
Not Related: The event is clearly related to other factors, such as the subject’s clinical state,
therapeutic interventions, or concomitant drugs administered to the subject.
Possibly Related: The event follows compatible temporal sequence from the time of beginning
the assigned study intervention, but could have been produced by other factors such as the
subject’s clinical state, therapeutic interventions, or concomitant drugs administered to the
subject.
Probably Related: The event follows a reasonable temporal sequence from the time of beginning
the assigned study intervention, and cannot be reasonably explained by other factors such as
the subject’s clinical state, therapeutic interventions, or concomitant drugs administered to
the subject.
Severity:
The severity, which is a measure of intensity, of clinical SAEs and laboratory abnormal-
ities will be recorded by the site investigator and categorized. The following guidelines will be used
to describe severity.
Mild: The event requires minimal or no treatment and does not interfere with the participant’s daily
activities.
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Moderate: The event results in a low level of inconvenience or concern with the therapeutic
measures. Moderate events may cause some interference with functioning.
Severe: The event interrupts a participant’s usual daily activity and may require systemic drug ther-
apy or other treatment. Severe events are usually potentially life-threatening or incapacitating.
Of note, the term “severe” does not necessarily equate to “serious”.
Expectedness of the Event:
SAEs will be evaluated as to whether their occurrence was expected
or unexpected. An SAE will be considered unexpected if the nature, severity, or frequency of the
event is not consistent with the risk information described for the study intervention.
Expected: An event is considered expected if it is known to be associated with the underlying
condition or is related to the study intervention and is mentioned in the protocol, informed
consent, or other study documents. An event may be expected despite the study subject’s
clinical state immediately prior to the event. Any symptom related to the primary diagnosis
for which the participant was initially hospitalized is expected. For example, symptoms
that would be expected for all of the FAAN-C conditions are fevers, vomiting, and diarrhea.
Expected symptoms for pneumonia are complaints like cough, shortness of breath, and trouble
breathing. Expected symptoms for urinary tract infection are complaints like abdominal pain
and dysuria. Expected symptoms for skin and soft tissue infections are complaints like pain,
swelling, and redness at the site of infection. Expected symptoms for gastroenteritis are
complaints like diarrhea.
Unexpected: An event is considered unexpected if there are no prior data linking this event with
either the condition or intervention under study or an event that occurred unexpectedly in the
course of treatment.
Treatment or Action Taken:
For each SAE, the site investigator will record whether an interven-
tion was required:
• Medical or surgical procedure
• Concomitant medication: started, changed, or discontinued
• Other, specify
• No action taken
Outcome of Event:
Finally, the site investigator will record the clinical outcome of each SAE as
follows:
• Death
• Recovered and the patient returned to baseline status
• Recovered with permanent sequelae
• Symptoms persist
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12.2.4
Data Collection Procedures for SAE
After patient randomization all SAEs will be recorded according to relatedness, severity, and
expectedness, as well as their duration and any treatment prescribed. Any medical condition present
at the time of randomization, recorded in the patient’s baseline history at study entry, which remains
unchanged or improves (unless the clinician feels it is clinically relevant), will not be recorded as an
SAE at subsequent evaluations. However, worsening of a medical condition that was present at the
time of randomization will be considered a new SAE, if it otherwise meets the SAE definition, and
reported.
SAEs will be coded using the MedDRA coding vocabulary. Coding will be done centrally at the
Data Coordinating Center as this requires specific training.
12.2.5
Unanticipated Problems (UP)
Unanticipated problems (UP) are defined as incidents, experiences, or outcomes that are unexpected,
related or possibly to participation in the study, and suggest that the research places subjects at a
greater risk of harm than was previously known or recognized. The site investigator will report
unanticipated problems to the Data Coordinating Center within 24 hours of becoming aware of
the event. A detailed completed report will be required to be sent to the Data Coordinating Center
within 3 working days of the event. After receipt of the complete report, the Data Coordinating
Center will notify PCORI promptly, but no later than 10 days after:
• reporting any serious unanticipated problems (e.g., serious adverse event, serious safety issue,
or other serious problem) relating the to the research study to the sponsor, DSMB, IRB, the
FDA, or other regulatory or oversight body; and
• Any decision, finding, recommendation, action, or direction of a DSMB, IRB, the FDA, or
any other regulatory or oversight body relating to any serious unanticipated problems (e.g.,
serious adverse event, serious safety issue, or other serious problem).
In accordance with local IRB requirements, the site investigator may be required to report such
unanticipated problems to the IRB in addition to notifying the Data Coordinating Center. In the event
that the medical monitor believes that such an event warrants emergent suspension of enrollment
in the trial, the Data Coordinating Center will notify the study investigator (Dr. Coon) and all site
investigators to cease enrollment in the trial.
12.2.6
Monitoring Serious Adverse Events
A qualified physician will be designated to fulfill the function of the medical monitor for this
study. Site investigators and/or research coordinators will report serious adverse events to the Data
Coordinating Center within 24 hours of becoming aware of the event. A detailed completed report
will be required to be sent to the Data Coordinating Center within 3 working days of the event, and
the medical monitor will assess all serious adverse events reported from site investigators.
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For each of these serious adverse events, the site investigator will provide sufficient medical history
and clinical details for a safety assessment to be made with regard to continuation of the trial. The
medical monitor will sign off on each SAE report after review. All SAE reports will be retained at
the Data Coordinating Center, and all SAE reports will be available for review by DSMB members
and PCORI staff. The SAE reporting process may be incorporated into the Electronic Data Capture
System in use for the study.
In the unlikely event that the medical monitor believes an unexpected and study-related SAE
warrants emergent cessation of enrollment in the trial, the DSMB chairperson will be immediately
consulted. If the DSMB chairperson concurs with the judgment of the medical monitor, or if the
DSMB chairperson cannot be reached expeditiously, the Data Coordinating Center will notify the
study investigator (Dr. Coon) and all site investigators to cease enrollment in the trial.
In accordance with local IRB requirements, the site investigator may be required to report such
events to the IRB in addition to notifying the Data Coordinating Center.
After notification of the PCORI Program Official or Project Officer, and the DSMB chairperson, of
serious, unexpected, and study-related adverse events or unanticipated problems (UP), decisions
will be made whether to continue the study without change, and whether to convene the entire
DSMB for an emergent meeting. If a decision is made to suspend enrollment in the trial, this will
be reported to the study investigator (Dr. Coon) and all clinical investigators, who will be instructed
to report this to their local IRB.
The DSMB will review medical errors and serious adverse events during scheduled DSMB meetings.
The Data Coordinating Center will prepare a Summary Report of medical errors and serious adverse
events.
12.2.7
Follow-up of Serious Adverse Events
All SAEs will be followed by the study team until the events are resolved, subject is lost to follow-up,
the SAE is otherwise explained or has stabilized, or 14 days have passed from the time of hospital
discharge.
13
Study Training
13.1
Study Training
A formal training program for investigators and research staff will be held prior to the start of
enrollment. The training program will cover regulatory topics and Good Clinical Practice. The
training will also provide in depth explanations regarding study procedures, clinical care, adverse
event reporting, data entry procedures, quality assurance, site monitoring, and the informed consent
process. A manual of operations will be provided to each investigator prior to the start of enrollment.
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The manual will detail specific information about the study procedures, regulatory information,
safety reporting, and other necessary information. Updates and revisions to the manual will be made
available electronically. The Data Coordinating Center, in collaboration with the study investigator
(Dr. Coon), will be the main contact for study questions.
14
Regulatory Considerations
14.1
Health Insurance Portability and Accountability Act
Data elements collected include the date of birth, date of admission, date of discharge, date of
medical visits, phone numbers, and email addresses. Prior to statistical analyses, dates will be used
to calculate patient age at the time of the study events. The final data sets (used for study analyses
and archived at the end of the study) will be de-identified, and will exclude these specific dates.
Data elements for race, ethnicity, and gender are also being collected. These demographic data are
required for Federal reporting purposes to delineate subject accrual by race, ethnicity, and gender.
For purposes of the Data Coordinating Center handling potential protected health information and
producing the de-identified research data sets that will be used for analyses, all study sites have been
offered a Business Associate Agreement with the University of Utah. Copies of executed Business
Associate Agreements are maintained at the Data Coordinating Center.
14.2
Inclusion of Women and Minorities
There will be no exclusion of patients based on gender, race, or ethnicity.
14.3
ClinicalTrials.gov Requirements
This trial will be registered at ClinicalTrials.gov in accordance with Federal regulations.
14.4
Retention of Records
For federally funded studies subject to the Common Rule, records relating to the research conducted
shall be retained for at least 3 years after completion of the research. Completion of the research
for this protocol should be anticipated to include planned primary and secondary analyses, as
well as subsequent derivative analyses. Completion of the research also entails completion of all
publications relating to the research. All records shall be accessible for inspection and copying
by authorized representatives of the regulatory authorities at reasonable times and in a reasonable
manner [45 CFR §46.115(b)].
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14.5
Public Use Data Set
After subject enrollment and follow-up have been completed, the Data Coordinating Center will
prepare a final study database for analysis. A releasable database will be produced and completely
de-identified in accordance with the definitions provided in the Health insurance Portability and
Accountability Act (HIPAA). Namely, all identifiers specified in HIPAA will be recoded in a manner
that will make it impossible to deduce or impute the specific identity of any patient. The database
will not contain any institutional identifiers.
The Data Coordinating Center will also prepare a data dictionary that provides a concise definition of
every data element included in the database. If specific data elements have idiosyncrasies that might
affect interpretation or analysis, this will be discussed in the dictionary document. In accordance
with policies determined by the investigators and funding sponsors, the releasable database will be
provided to users in electronic form.
15
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