Pediatric Dose Optimization for Seizures in EMS (PediDOSE)
Phase: PHASE3
Conditions: Seizures
Sponsor: Stanford University

Pediatric Dose Optimization for Seizures in EMS
(PediDOSE)
PECARN Protocol Number 052
Pediatric Emergency Care Applied Research Network
National Institute of Neurological Disorders and Stroke (NINDS)
Health Resources and Services Administration (HRSA)
Maternal and Child Health Bureau (MCHB)
Emergency Medical Services for Children (EMSC) Program
Protocol Version 1.04
Version Date: June 3, 2022
Printing Date: June 3, 2022
IND: 156119
NCT: 05121324

Copyright © 2022. University of Utah School of Medicine on behalf of the Principal Investiga-
tor, Manish I. Shah, M.D., M.S. and the Pediatric Emergency Care Applied Research Network
(PECARN). All rights reserved.
This protocol is PECARN Protocol Number 052, and has been authored by Manish I. Shah, M.D.,
M.S., Baylor College of Medicine, for implementation with the PECARN investigators. This study
is supported by U01-NS114042 awarded to Baylor College of Medicine (PI:Manish I. Shah, M.D.,
M.S.) by the National Institute of Neurological Disorders and Stroke (NINDS).
The PECARN research network is supported by the Health Resources and Services Adminis-
tration (HRSA) of the U.S. Department of Health and Human Services (HHS), in the Maternal
and Child Health Bureau (MCHB), under the Emergency Medical Services for Children (EMSC)
program through the following cooperative agreements: DCC-University of Utah (UJ5MC30824),
GLEMSCRN-Nationwide Children’s Hospital (U03MC28844), HOMERUN-Cincinnati Children’s
Hospital Medical Center (U03MC22684), PEMNEWS-Columbia University Medical Center (U03MC00007),
PRIME-University of California at Davis Medical Center (U03MC00001), CHaMP node – State
University of New York at Buffalo (U03MC33154), WPEMR – Seattle Children’s Hospital
(U03MC33156), and SPARC- Rhode Island Hospital/Hasbro Children’s Hospital (U03MC33155).
This information or content and conclusions are those of the author and should not be construed as
the official position or policy of, nor should any endorsements be inferred by HRSA, HHS or the
U.S. Government.
This document was prepared by the PECARN Data Coordinating Center (DCC) located at the
University of Utah School of Medicine, Salt Lake City, Utah. The document was written and
typeset using LATEX 2ε. The DCC at the University of Utah is supported by Cooperative Agreement
UJ5MC30824 from the Emergency Medical Services for Children (EMSC) Program, Maternal and
Child Health Bureau, Health Resources and Services Administration.

PROTOCOL TITLE:
Pediatric Dose Optimization for Seizures in EMS
Short Title: PediDOSE
PECARN Protocol Number: 052
Lead Investigator and Author:
Manish I. Shah, M.D., M.S.
Baylor College of Medicine
Protocol Version: 1.04
Version Date: June 3, 2022
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:

THIS PAGE IS INTENTIONALLY BLANK.

Contents
List of Tables
7
List of Figures
7
1
Study Summary
8
1.1
Study Objective and Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
1.1.1
Primary Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
1.1.2
Secondary Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
1.1.3
Exploratory Outcomes
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
1.1.4
Safety Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
2
Rationale and Background
10
3
Subject Eligibility, Accrual and Study Duration
11
3.1
Eligibility criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
3.2
Subject Accrual and Study Duration . . . . . . . . . . . . . . . . . . . . . . . . .
11
3.3
Age De-escalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
4
Study Procedures
13
4.1
Stepped Wedge Design and Randomization of EMS Agencies . . . . . . . . . . . .
13
4.2
Identification of Patients
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
4.3
Study Arms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
5
Data Collection
15
5.1
Prehospital Data Collection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
5.1.1
EMS Database
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
5.1.2
Paramedic Self-Report . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
5.2
Data Collection During Hospitalization . . . . . . . . . . . . . . . . . . . . . . . .
19
5.2.1
Hospital Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
5.2.2
Rapid Response EEG (RR-EEG) Data . . . . . . . . . . . . . . . . . . . .
19
6
Statistical Summary
20
6.1
Sample Size Justification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
6.2
Data Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
6.2.1
Study Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
6.2.2
Subgroup Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
6.2.3
Safety Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
6.2.4
Safety and Effectiveness Interim Monitoring . . . . . . . . . . . . . . . . .
22
6.2.5
Missing Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
6.2.6
Population for Analyses
. . . . . . . . . . . . . . . . . . . . . . . . . . .
23
7
Data Management
23
7.1
Clinical Site Data Management . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
7.2
Data Coordinating Center . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
5

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7.2.1
Data Center Description
. . . . . . . . . . . . . . . . . . . . . . . . . . .
23
7.2.2
Facility, Hardware, Storage, Data Backup and System Availability . . . . .
24
7.2.3
Security, Support, Encryption, and Confidentiality . . . . . . . . . . . . . .
24
7.3
Electronic Data Capture System
. . . . . . . . . . . . . . . . . . . . . . . . . . .
25
8
Study Site Monitoring
25
8.1
Site Monitoring Plan
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
25
8.2
Clinical Site Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
8.3
Remote Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
8.4
Record Access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
9
Protection of Human Subjects
27
9.1
Risks to Human Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
9.1.1
Potential Risks of Patient Participation . . . . . . . . . . . . . . . . . . . .
27
9.1.2
Potential Risks to EMS Providers
. . . . . . . . . . . . . . . . . . . . . .
27
9.2
Adequacy of Protection Against Risks . . . . . . . . . . . . . . . . . . . . . . . .
28
9.2.1
Exception from Informed Consent (EFIC) . . . . . . . . . . . . . . . . . .
28
9.2.2
Opt Out, Notification, and Withdrawal . . . . . . . . . . . . . . . . . . . .
30
9.2.3
Collection of Mortality and Outcome Data on All Eligible Subjects . . . . .
32
9.2.4
Vulnerable Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
9.2.5
Institutional Review Board and Human Research Protection
. . . . . . . .
34
9.2.6
Protections Against Risk . . . . . . . . . . . . . . . . . . . . . . . . . . .
34
9.3
Potential Benefits of Proposed Research . . . . . . . . . . . . . . . . . . . . . . .
34
9.4
Importance of the Knowledge to be Gained
. . . . . . . . . . . . . . . . . . . . .
34
10 Data and Safety Monitoring Plan
35
10.1 Data Safety Monitoring Board (DSMB)
. . . . . . . . . . . . . . . . . . . . . . .
35
10.2 Adverse Event Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35
10.2.1 Definition of Adverse Event and Serious Adverse Event . . . . . . . . . . .
35
10.2.2 Classification of Adverse Events (Relatedness and Expectedness . . . . . .
36
10.2.3 Data Collection Procedures for Adverse Events . . . . . . . . . . . . . . .
38
10.2.4 Unanticipated Problems (UP) . . . . . . . . . . . . . . . . . . . . . . . . .
38
10.2.5 Monitoring Serious Adverse Events
. . . . . . . . . . . . . . . . . . . . .
38
10.2.6 Follow-up of Serious, Unexpected and Related Adverse Events . . . . . . .
39
10.2.7 Reporting to the Food and Drug Administration . . . . . . . . . . . . . . .
39
11 Study Training
39
12 Regulatory Considerations
40
12.1 Food and Drug Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40
12.2 Health Insurance Portability and Accountability Act . . . . . . . . . . . . . . . . .
41
12.3 Inclusion of Women and Minorities . . . . . . . . . . . . . . . . . . . . . . . . . .
41
12.4 Clinical Trial Registration Requirements . . . . . . . . . . . . . . . . . . . . . . .
41
12.5 Retention of Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41
12.6 Public Use Data Set . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41
PediDOSE Protocol Version 1.04
Protocol Version Date: June 3, 2022
The EMSC Pediatric Emergency Care Applied Research Network

13 Bibliography
42
any floating tables or figures, you can comment these lines out.
List of Tables
1
Age de-escalation strategy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
2
PediDOSE data variables and sources. . . . . . . . . . . . . . . . . . . . . . . . .
18
List of Figures
1
Stepped wedge design and study timeline. . . . . . . . . . . . . . . . . . . . . . .
13
2
Study arms being assessed in PediDOSE trial. . . . . . . . . . . . . . . . . . . . .
16
7

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Abstract
Seizures are one of the most common reasons why bystanders call Emergency Medical
Services (EMS) for a child, and current practice frequently fails due to under-dosing and
delayed delivery of anti-seizure medication. Benzodiazepines, such as midazolam, given in
the nose or as a muscular injection are the first line treatment for seizures. Unfortunately,
one-third of children having a paramedic-witnessed seizure have ongoing seizures on arrival to
the emergency department (ED) because an inadequate and delayed dose of midazolam fails to
stop seizures. Children who continue to seize have seizures that are harder to stop, and this puts
them at risk for not breathing and having brain damage. Reducing this risk requires equipping
paramedics with a simplified method for rapidly determining and administering a therapeutic
dose of medication. Paramedics suggest simplifying midazolam dosing by eliminating the
error-prone, sequential calculations required to determine a weight-based dose under stressful
conditions. Standardized, age-based dosing may be simpler, faster and more effective, without
compromising safety.
The overall objective of the Pediatric Dose Optimization for Seizures in EMS (Pedi- DOSE)
study is to measure the impact of standardized EMS midazolam dosing on seizure treatment
effectiveness and safety. To achieve this objective, we will conduct a large EMS trial in the
Pediatric Emergency Care Research Network (PECARN) to implement standardized, age-
based midazolam dosing for pediatric seizures in EMS systems in 20 cities. We believe
that implementation will stop more seizures before children arrive at EDs without increasing
respiratory failure rates. The first aim of this study is to compare the impact of standardized
EMS midazolam dosing relative to conventional dosing on seizure cessation. We hypothesize
that giving a standardized midazolam dose based on age will allow paramedics to stop a child’s
seizure faster than conventional dosing with current practice. The second aim of this study is
to determine how often children stop breathing or ineffectively breathe after implementation
of standardized EMS midazolam dosing. We hypothesize that standardized EMS midazolam
dosing will be associated with no difference in slow or absent breathing relative to conventional
dosing with current practice. If this study demonstrates that standardized, age-based midazolam
dosing is both safe and more effective than current practice, the potential impact of this study
is a paradigm shift in the treatment of pediatric seizures that can be easily implemented in
emergency medical services (EMS) systems across the country.
1
Study Summary
This study is a Phase 3, multi-center, stepped wedge trial of midazolam dosing for seizures in pedi-
atric patients in the Emergency Medical Services (EMS) setting. It randomizes the timing of each
of the participating EMS agencies at 20 different sites to switch from conventional, weight-based
dosing to standardized, age-based dosing, so that every EMS agency switches from conventional to
standardized dosing over a 4-year enrollment period in this 5-year study. Federal exception from
informed consent (EFIC) procedures will be used for enrollment.
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1.1
Study Objective and Outcomes
Aim 1 - Primary Objective (Effectiveness)
The primary objective of this study is to compare the impact of standardized EMS midazolam
dosing on seizure cessation. We hypothesize that standardized intramuscular (IM) or intranasal (IN)
midazolam dosing of approximately 0.2 mg/kg, based on age-based estimates for weight, will be
associated with lower frequency of active seizures upon ED arrival, when compared to conventional
dosing with calculations from estimated weights.
Aim 2 - Secondary Objective (Safety)
The secondary objective of this study is to compare the frequency of respiratory failure after
implementation of standardized EMS midazolam dosing for pediatric seizures. We hypothesize that
standardized dosing will not increase respiratory failure when compared to conventional dosing.
1.1.1
Primary Outcome
The primary outcome is the proportion of patients having a seizure on ED arrival. To assess the
primary outcome in patients who are completely unresponsive to verbal or painful stimuli, a rapid
response electroencephalogram (EEG) recording device will be applied to children in whom the
device is approved by the Food and Drug Administration (FDA), which is currently ages 2–13 years
old. Once the device is FDA-approved for use in 6–23 month olds, it will also be applied to these
study-eligible participants.
1.1.2
Secondary Outcomes
The two secondary outcomes are:
• Proportion of patients with respiratory failure in the prehospital setting or within 30 minutes
of ED arrival, defined as having received bag valve mask (BVM) ventilation, bi-level positive
airway pressure (BiPAP), continuous positive airway pressure (CPAP), or placement of a
supraglottic airway (SGA) or endotracheal intubation (ETI);
• Time to first midazolam administration after paramedic arrival to the scene.
1.1.3
Exploratory Outcomes
Exploratory outcomes include:
• Time to seizure cessation in the ED, if still having a seizure on ED arrival;
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• Dose/route adherence, defined as receiving an intranasal (IN) or intramuscular (IM) mida-
zolam dose within 30% of 0.2 mg/kg (0.14–0.26 mg/kg), calculated from the measured ED
weight.
1.1.4
Safety Outcomes
Safety outcomes include:
• Life threatening hypotension
• Life threatening cardiac arrhythmia
• Depressed level of consciousness
2
Rationale and Background
Emergency Medical Services (EMS) frequently transports children with active seizures children,
but treatment delays make seizures difficult to stop and lead to respiratory failure, brain damage
and death.1, 6, 7, 13, 23, 26, 31, 34, 36Immediate delivery of the correct benzodiazepine dose is essential to
effectively and safely treat pediatric prehospital seizures, and an evidence-based guideline (EBG)
recommends the initial use of intramuscular (IM) or intranasal (IN) benzodiazepines over other
routes, since obtaining intravenous (IV) access is time-consuming and challenging during an active
seizure.6, 13, 17, 21–23, 30
Our prior work has shown that paramedics are more likely to administer the first dose of midazolam
via the preferred IN/IM routes after implementing a protocol consistent with the EBG. However,
dosing errors, treatment failure (still having a seizure upon ED arrival), and delays in benzodiazepine
administration after scene arrival are still common.31 Paramedics have suggested that making
equipment available for IN/IM medication administration, standardizing doses for preferred routes,
eliminating dose calculations, and removing protocol ambiguities would enhance protocol adherence
and improve outcomes.3
The Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) evaluated standardized
doses of IV lorazepam and IM midazolam in adults and children approximately 2 years and older,
and the results from RAMPART weighed heavily in the EBG recommendations.32 Though the focus
of RAMPART was to compare different routes of benzodiazepines in terminating status epilepticus
before ED arrival, it also demonstrated that standardized dosing is feasible in children, though larger
pediatrics studies are needed.32 Other studies have demonstrated that midazolam at IN/IM doses
of 0.2–0.5 mg/kg are effective and safe in children in the ED, but this has not been studied in a
prehospital setting.11, 25, 28 In EMS, the high rates of pediatric under-dosing and high frequency
of seizures on ED arrival highlight how optimizing dose administration could improve outcomes.
A potentially more effective approach than current practice is to eliminate calculations through
standardized, volume-based dosing based on a child’s age15, 16, 19, 20, 33 Since respiratory failure may
be due to prolonged status epilepticus rather than benzodiazepine overdose, using this standardized
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Protocol 052 (Shah)
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approach may also be significantly safer than conventional dosing.
3
Subject Eligibility, Accrual and Study Duration
3.1
Eligibility criteria.
Inclusion criteria for the EMS treatment protocol are:
• Age ≥6 months* to ≤13 years; AND
• Witnessed by a paramedic to be having a seizure, regardless of seizure type or duration; AND
• Transported by an EMS agency participating in this study.
*(The lower age limit eligible to receive the standardized midazolam dose will be iteratively modi-
fied using an age de-escalation approach, described in more detail below. All patients in the age
range noted above are eligible for study inclusion, regardless of whether the EMS agency is using
conventional dosing or standardized dosing at a given point in time.)
Exclusion criteria are:
• A prior history of a benzodiazepine allergy; OR
• Known or presumed pregnancy; OR
• Severe growth restriction based on the paramedic’s subjective assessment.
Age will be determined based on the bystander’s report to the paramedic at the scene. If the
bystander does not know the patient’s age or no bystander is present, the paramedic will use
whatever length-based tape the EMS agency uses to estimate the age.
3.2
Subject Accrual and Study Duration
PediDOSE utilizes a stepped wedge design to randomize PECARN EMS affiliates in 20 cities to
implement standardized dosing in a staggered manner, every four months. Subject accrual will
occur over four years. We anticipate that we will enroll up to 6,700 subjects over this four year
period.
3.3
Age De-escalation
For the doses utilized in the EMS protocol for the intervention, we will use an age de-escalation
strategy to balance the need to maximize safety in the youngest pediatric patients while also
generating evidence on the effectiveness of standardized, age-based dosing in these patients.
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At the beginning of Year 1 of patient enrollment, all sites will utilize conventional dosing in their
EMS agencies. Conventional dosing is what the EMS agency is already doing to determine the dose
before the study begins, and agencies typically use manual calculation of the midazolam dose based
on the patient’s weight, using an estimate from a length-based tape, followed by conversion of that
dose to a volume to be administered.
When the initial sites implement standardized dosing in Year 1, they will do so only for 2–13 year
old patients; any patient <2 years old will still continue to be dosed according to conventional
dosing. Standardized dosing utilizes a dose of approximately 0.2 mg/kg IN/IM midazolam and
eliminates all calculations, since the volumetric dose is based on the bystander-reported patient age.
For the study, all EMS agencies will utilize the 5 mg/ml concentration of midazolam in order to
standardize the age-based volume of medication that is administered via the IN or IM routes across
all sites.
Near the end of each year of enrollment, the data safety monitoring board (DSMB) will evaluate
patient safety data on those already enrolled to determine if it is safe to de-escalate the age in the
subsequent year(s) of enrollment (Years 2, 3, and 4). If the DSMB approves de-escalation for the
upcoming year(s) of enrollment, the EMS agencies that subsequently implement standardized dosing
will use the revised lower age limit for standardized dosing. All EMS agencies that had already
implemented standardized dosing must begin utilizing the revised lower age limit within 12 months
of DSMB approval; this additional time is allowed so that the EMS agency can coordinate the
change with their usual periodic, system-wide patient care protocol updates. In-person paramedic
training will not be required when age de-escalation occurs in EMS agencies that have already
switched to standardized dosing. Online/printed EMS protocols and decision support tools will be
updated to reflect the change. Paramedics will also be notified of the change in accordance with
their EMS agency’s communication policy regarding protocol updates.
At the beginning of Year 3 of patient enrollment, if the DSMB deems that it is safe to do so based
on data from patients already enrolled, a fourth dose of midazolam (1.25 mg = 0.25 mL) will be
added for 12–16 month old patients. The lower age limit of enrollment will then decrease to 6
months at the beginning of Year 4 of patient enrollment, if the DSMB deems that it is safe to do so.
By the end of the 4-year patient enrollment period, all sites will have switched from conventional to
standardized dosing for doses and age ranges that the DSMB has determined to be safe.
Data will be collected on all eligible 6 month to 13 year old patients during the entire enrollment
period, regardless of the status of age de-escalation, because younger patients who are being treated
based on conventional dosing are part of the comparison group relative to those being treated under
the clinical EMS treatment protocol that utilizes standardized midazolam dosing. Collecting data
on these younger patients at all phases of the study is necessary to sufficiently answer the study
question, even if they are being treated using conventional dosing.
The overall age de-escalation strategy is summarized below:
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Age
Year of Patient
Enrollment
Estimated % of Pediatric Patients
Having a Seizure Who Are Eligible
for PediDOSE
Standardized Dose for
PediDOSE
12–13 years
Year 1
8%
10 mg = 2 mL
6–11 years
Year 1
47%
5 mg = 1 mL
2–5 years
Year 1
36%
2.5 mg = 0.5 mL
17–23 months*
Year 2
4%
2.5 mg = 0.5 mL
12–16 months*
Year 3
2%
1.25 mg = 0.25 mL
6–11 months*
Year 4
3%
1.25 mg = 0.25 mL
*Contingent upon DSMB approval after evaluation of patient safety data
Table 1: Age de-escalation strategy.
4
Study Procedures
4.1
Stepped Wedge Design and Randomization of EMS Agencies
PediDOSE utilizes a stepped wedge (SW) design (Figure 1) among the PECARN EMS affiliates to
implement standardized dosing in a staggered manner at an agency, every 2 months.12 Due to the
timing of EFIC, the stepped wedge will be implemented in two stages of 10. With the SW design,
standardized dosing will be staggered at all 20 sites after a 4-month training period.
Figure 1: Stepped wedge design and study timeline.
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The stepped wedge design randomizes the order in which the sites will transition from conventional
to standardized dosing within the sites of each cohort (the sites that start earlier and the sites
that start later). Following the approximate timeline in the figure, approximately every 4 months
per cohort of enrollment, the PECARN DCC will provide notification about randomization to a
city’s participating EMS agencies to make the change from conventional weight-based dosing to
standardized age-based dosing. No individual patient randomization will occur. The allocation
will be concealed regarding the timing of when the EMS agency will switch from conventional to
standardized dosing, such that agencies and investigators will not know when their transition will
occur until they receive notification about randomization. In order to allow for the system-wide
changes required for implementation, the EMS agency leadership, other site personnel, and the
study PI will be informed up to 2 months prior to beginning the 4 month training period, after which
the new protocol will be implemented. The ED staff may be aware of the randomization status of
the local EMS agency or agencies participating in the study.
4.2
Identification of Patients
In many instances, the research coordinator (RC) will be present in EDs directly affiliated with the
study when the EMS agency transports the child, and they will screen EMS arrivals for eligible
patients. We will attempt to gather EMS data about children who were transported to non-affiliated
emergency departments (EDs) for a seizure to determine trial eligibility. A non-affiliated ED
is defined as other EDs in metropolitan areas where the study is occurring that lack research
coordinator (RC) coverage for this study. To assure data capture when the RC is not available
to have a direct conversation with the paramedic after patient hand-off, or when the patient is
transported to a non-affiliated ED, the paramedics will either call a phone number that they can
access anytime to notify research staff that they have transported a potentially eligible patient or
by direct data entry link. Data that is collected directly from the paramedic about the prehospital
care of the enrolled patient is referred to as the “paramedic self-report.” The study staff will verify
eligibility criteria when they obtain this paramedic self-report either in-person, over the phone, or
by direct data entry by the paramedic.
Since it is possible that the paramedic may not have a chance to directly communicate with the RC
between patient hand-off and when they go back into service, the RC will also review daily data
from the EMS agency database to identify patients who are potentially eligible to be included in the
study. Agencies that do not provide database access to their affiliated hospital will securely transfer
data for all pediatric seizure transports to the coordinator and site investigator for the purpose of
eligibility screening. The RC will review the limited EMS data necessary to confirm that the patient
meets all inclusion criteria, including verification that they were having a seizure in the presence
of a paramedic. These patients will be included in the DCC database, and if exclusion criteria are
present, those criteria will also be included in the DCC database. Eligible patients who meet all
eligibility criteria will have data collected in accordance with the choice that their parent, guardian,
legally authorized representative or other adult family member has made during the therapeutic time
window or at the time of trial notification, as described in Section 5 on the next page.
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4.3
Study Arms
The two study arms are schematically shown in Figure 2 on the following page. In the conventional
dosing arm (a), EMS agencies will continue to utilize the weight–based drug dosing method that
is part of current practice in accordance with their existing EMS protocol. Typically, paramedics
determine a patient’s weight using whatever system their EMS agency uses (Broselow, Handtevy or
other mechanism), choose a route of administration [IM, IN, IV, or intraosseous (IO)] and perform
several calculations to determine the dose of medication to deliver. The standardized dosing arm (b)
reduces the choice of routes to IM or IN, and eliminates calculations of drug dose. The drug dose is
based on age of the child, as determined from bystanders or estimated by the paramedic.
All participating EMS agencies have agreed to continue their current protocol until randomization,
and to use the standardized dosing regimen after randomization, training and implementation. The
standardized midazolam dose is approximately 0.2 mg/kg (range: 0.14–0.26 mg/kg), based on the
published EBG for pediatric seizure management.30 The four dose options ensure the weight-based
dose is within 30% of the 0.2 mg/kg EBG-recommended dose. The estimated doses for the proposed
study are based on the 50th percentile weights-for-age from standardized Centers for Disease
Control growth charts. After implementation, a sticker, card, and/or other decision support tool
compatible with what paramedics already access in their EMS agency for dosing guidance will be
located in proximity to where the midazolam is stored, so that the standardized doses for each age
range are readily available when drawing up the medication.
5
Data Collection
The sources of all data variables that will be collected are shown in Table 2 on page 18. Data to be
collected for this study includes:
• Prehospital Data from both the EMS database and the paramedic self-report: To be collected
for all enrolled patients regardless of destination of transport
• Hospital Data including rapid response electroencephalogram (RR-EEG) and hospital records:
To be collected for all patients transported to a hospital affiliated with the study.
• Publicly available data: To be collected, as needed, to confirm mortality information for
participants who died and access to hospital records is not available to investigators due to
withdrawal or transportation to a non-affiliated ED.
Parents, guardians, legally authorized representatives, and adult family members may have the
opportunity to decline trial participation during the therapeutic time window, if feasible, and will
have the opportunity to decline ongoing trial participation, including data collection, at the time
of notification about the trial. If a parent, guardian, legally authorized representative, or adult
family member declines further data collection, this date/time will be noted on the informed consent
document and no data will be collected after the date/time of participant withdrawal. If, despite the
investigator’s best efforts, the investigator is not able to contact a parent, guardian, legally authorized
representative, or adult family member during the therapeutic time window and notification about
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(a) Conventional treatment (control).
(b) Standardized treatment (intervention).
Figure 2: Study arms being assessed in PediDOSE trial.
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the trial at the earliest feasible opportunity is not successful, participant data will be collected as
described above.
5.1
Prehospital Data Collection
5.1.1
EMS Database
Paramedics already capture the majority of EMS data necessary for this study during usual doc-
umentation of patient care in the EMS agency’s electronic medical record. For sites that do not
have direct access to this data, the EMS agency will securely transfer the data for all pediatric
seizure transports to the study team regularly. The research coordinator at the site will enter relevant
information into a secure electronic data capture (EDC) system that is housed at the PECARN Data
Coordinating Center (DCC), based at the University of Utah. Data from the EMS record includes
variables such as dates and times of the incident, medication administration, patient demographics
and past medical history.
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Table 2: PediDOSE data variables and sources.
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5.1.2
Paramedic Self-Report
Upon arrival to the ED, a study-affiliated research coordinator, if present, will collect paramedic
self-reported data not routinely documented in the electronic EMS record. If the paramedic arrives
at an ED where the coordinator is not available, the paramedic will get in touch with the research
staff by either calling a phone number or via direct data entry using a QR code or link.. Both
the phone number and the QR code will be accessible on all paramedic vehicles, so that they can
notify research staff anytime that they have transported a potentially eligible patient. The study staff
will verify eligibility criteria when they obtain this paramedic self-report either in-person, over the
phone, or online in REDCap. The paramedic self-report will also include questions about whether it
was feasible or not for the paramedic to attempt to contact the parent, guardian, or legally authorized
representative about the study. The paramedic self-report will also include a question about whether
the parent expressed an objection to further data collection for the study for their child and whether
they objected to the placement of the RR-EEG.
5.2
Data Collection During Hospitalization
5.2.1
Hospital Records
EMS and hospital records will be linked locally at each site based on patient identifiers including
last name, first name, destination of transport, date of birth and date/time of ED arrival. Study data
will be coded, so the patient’s name is not transmitted to the DCC. The RC will collect ED-based
data, disposition, and length of stay data from the hospital electronic records. The sample size is
based on patients having a paramedic-witnessed seizure who are transported to EDs affiliated with
the study. For patients transported to non-affiliated hospitals, the investigators will only attempt to
gather EMS and paramedic self-report data.
5.2.2
Rapid Response EEG (RR-EEG) Data
To assess the primary outcome, a study team member or clinical personnel will apply the RR-EEG
recording device to a sub-set of enrolled participants upon arrival at a study-affiliated ED, unless
parent/guardian objection to participation has been received prior to or upon arrival. The RR-EEG
will be placed, regardless of randomization status of the EMS agency, if the patient meets one or
more of the following criteria:
1. The patient is actively having a seizure upon ED arrival, based on the parent/guardian,
physician, or nurse’s assessment OR
2. The patient is unresponsive to light touch or voice
These patients will have the device in place while unresponsive in the ED. The rapid response device
records EEG data that are then uploaded to a cloud-based server. The device is synchronized to local
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time with settings that can be used to uniquely identify the site, so that the date/time stamp from the
device can be used to link the EEG data for the study with a unique patient, based on their date/time
of ED arrival at the study site. An epileptologist co-investigator will read the EEG waveform output
to definitively assess the primary outcome, but this will not be done in real-time. The epileptologists
will be blinded to the clinical care that occurred in the ED when making their initial assessment
of whether or not the patient was having a seizure on ED arrival. For patients who are 6–13 years
old, 1 epileptologist will read approximately 90% of these RR-EEGs; however, approximately 10%
of these RR-EEGs will be read by 2 epileptologists in order to determine inter-rater reliability.
All RR-EEG output on study subjects <6 years old will be read by 2 epileptologists. If there
is a discrepancy in the read between these 2 epileptologists, a third epileptologist will make a
tie-breaking determination of the RR-EEG output.
The treating ED attending physician and triage nurse will also document whether the patient was
having a seizure on ED arrival. A hierarchy of the preferred source of primary outcome assessment
will be provided in the Statistical Analysis Plan.
6
Statistical Summary
6.1
Sample Size Justification
The frequency of seizures on ED arrival was estimated through simulation based on hypothesized
frequencies for both conventional dosing and standardized dosing and based on prior data.29, 31 The
simulations used for calculating the sample size using the stepped wedge (SW) design accounted
for the site-to-site variability in enrollment. Only randomization sequences that have an expected
enrollment size for the conventional and standardized dosing arms within 5% of each other at the
end of the trial will be considered. We expect to see 1,210 active pediatric seizure cases per year.
Seizure cases that are observed during the SW transition periods are not counted towards either
arm. Accounting for an 8% intra-cluster correlation, up to 10% lack of identification of eligible
patients and exclusion of seizures during transition periods, we expect to see at least 820 seizure
cases per year eligible for analyses. Based on this and the stepped wedge design as described above,
we approximate 87% power to detect a difference in the rate of seizures on ED arrival rate between
39% in the conventional dosing arm and 29% in the standardized dosing arm in the 6 month – 13
year old patients.
6.2
Data Analyses
6.2.1
Study Outcomes
The primary outcome of seizures on ED arrival will be analyzed using a mixed logistic regression
with a random effect for site. The main predictor of interest is arm (conventional weight-based
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vs. standardized age-based dosing). We will control for the logistic regression with appropriate
covariates:
• Presence vs. absence of fever;
• New-onset seizure vs. previous history of seizures;
• Receipt of bystander-administered benzodiazepine prior to EMS arrival;
• Time (months) since study start;
• Sex;
• Age;
• Presence or absence of hypoglycemia (glucose <60 mg/dL).
The secondary outcomes (respiratory failure and time to first midazolam administration) and
exploratory outcome (time to seizure cessation) will be analyzed in a similar framework as the
primary outcome. For the exploratory measure of dose/route adherence with respect to these
guidelines, we define adherence as receiving a first dose of EMS administered midazolam within
30% of the expected dose based on the protocol the paramedic is using at the time. Subjects will be
considered adherent or non-adherent.
The study outcomes analyses will only include subjects who have not previously been in the study.
Repeated events for the same subject will be identified by the identifiers used for record linkage,
and only the initial event in the study will be included in the analyses of outcomes.
6.2.2
Subgroup Analyses
Subgroups of interest include:
• Method of dose determination
• Presence vs absence of fever
• New-onset seizure vs previous history of seizure
• Receipt of bystander-administered benzodiazepine prior to EMS arrival
• Route used to administer midazolam
• Sex
• Age
• Presence or absence of hypoglycemia
• Race/ethnicity
6.2.3
Safety Outcomes
Safety outcomes include:
• Life threatening hypotension
• Life threatening cardiac arrhythmia
• Depressed level of consciousness
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These safety outcomes are defined in more detail in the ‘Classification of Adverse Events’ section.
Life threatening hypotension and cardiac arrhythmia will be categorized as an occurred/not occurred
event and will be compared between arms using a Mantel-Haenszel test, stratified by clinical center.
Fisher’s exact test will be used in cases of small counts. For depressed level of consciousness,
Glasgow Coma Scores (GCS) will be assessed upon ED arrival and then regularly until departure
from the ED and as needed to determine return to normal. We will compare return to normal
between arms.
6.2.4
Safety and Effectiveness Interim Monitoring
The DCC will perform limited interim safety analysis at the end of each year of patient enrollment
in order to prepare a report for the DSMB to determine whether or not the lower age limit for using
standardized dosing can be de-escalated. The DCC will perform an interim safety analysis for the
DSMB after 1.5 years of enrollment, comparing adverse events, including serious adverse events,
between study arms using a Mantel-Haenszel test, stratified by clinical center and baseline severity
of symptoms. An interim safety and effectiveness analysis will be provided to the DSMB after 3
years, using Lan-DeMets spending functions corresponding to O’Brien-Fleming type boundaries.8
Unlike a traditional randomized trial with approximately equal numbers of intervention and control
patients throughout, the SW design results in more control patients at the beginning of enrollment
and more intervention patients towards the end. Due to this, we will use Hemming, Lilford, and
Girling’s method to appropriately spend alpha.14 No formal futility monitoring is anticipated.
6.2.5
Missing Data
Per the intention-to-treat principle, subjects who withdraw from the study or are lost to follow-up
will have all available data used in the analysis. In the event that a substantial number of subjects
are withdrawn or lost to follow-up, baseline characteristics and available information on hospital
course will be reviewed and compared to subjects not withdrawn or lost, to assess empirically if
these subjects differ from those remaining in the study for the scheduled treatment and follow-up
time.
The outcomes are collected from the time period of prehospital care and the hospital stay, and will
not require patient follow up beyond the hospital stay. Due to the ability to find the outcomes in the
electronic health record, we anticipate very low missing rates for primary and secondary analyses.
For this reason, the primary and secondary analyses will use complete case analyses if there are
minimal missing data. If the rate of missing data is above an unreasonable threshold as defined
in the Statistical Analysis Plan, we will perform multiple imputation using sequential regression
methods to perform the analyses.
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6.2.6
Population for Analyses
Patients transported to an ED that is not affiliated with the study will be analyzed separately for
the limited primary, and safety outcomes that can be assessed. This will be used to demonstrate
whether or not the patients who EMS transported to affiliated EDs had comparable outcomes to
those they brought to non-affiliated EDs. Patients will be excluded from study analysis (primary,
secondary, exploratory and safety) if they meet at least one of the following criteria, as reported by
the bystander, determined by the paramedic, or noted in the hospital medical record:
• Presumed or known traumatic head injury within 24 hours of the seizure; OR
• Any prior history of psychogenic, non-epileptic seizures; OR
• Ventilator dependence at the time of the seizure; OR
• Intentional or unintentional ingestion of a medication or substance <24 hours prior to EMS
care, if that medication or substance has the potential to cause seizures or altered mental
status; OR
• Presence of absence seizures during EMS or ED care on the date of enrollment; OR
• Previously enrolled in the study.
7
Data Management
7.1
Clinical Site Data Management
Each clinical site will maintain study records in locked filing cabinets. The site will maintain an
Essential Documents Binder, which may be in paper or electronic form.
7.2
Data Coordinating Center
7.2.1
Data Center Description
The Data Coordinating Center (DCC) in the Department of Pediatrics at the University of Utah
School of Medicine provides data coordination and management services for PECARN and a variety
of other national research networks. Anchoring these services is a state-of-the-art, energy efficient
data center. The data center facility supports more than 3500 users around the country and will
provide a secure, reliable, enterprise-wide infrastructure for delivering mission critical DCC systems
and services to PECARN.
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7.2.2
Facility, Hardware, Storage, Data Backup and System Availability
The data center was built using industry standards and energy efficient cooling solutions. The data
center is cooled by Liquid Cooling Package (LCP) inline cooling technology, providing the desired
efficiency, redundancy and modularity. The LCP utilizes a hot/cold aisle design that allows for
even air distribution to minimize hot spots. The data center’s electrical power system contains an
uninterruptible power supply with a diesel backup generator. The data center is protected with
an FM-200 backed fire suppression system, which provides waterless fire suppression without
leaving behind residue or particulate. Enhanced security measures are implemented to safeguard
the equipment and the data within in it. Security measures are enforced 24 hours a day, seven days
a week, 365 days a year by a combination of on-premise security guards, University police officers,
and video surveillance.
The data center has a virtualized environment. This environment consists of more than 415 virtual
servers across 25 host servers. Virtualization provides key advantages: (1) High availability – in the
event of hardware failure, virtual machines automatically restart on healthy resources, minimizing
impact to end-users; (2) Flexible infrastructure – compute and storage is seamlessly scaled as current
needs change; (3) Rapid deployment – new resources are provisioned on-demand.
Production servers running mission critical applications are clustered and configured for failover
events across multiple clusters. Entire servers are backed-up to a dedicated infrastructure. The
backup repositories are encrypted-at-rest using AES-256. The storage area networking applications,
clusters, and switch-to-switch links are highly redundant. Incremental backups of data occur
Monday through Friday. A full data backup occurs weekly. Full backups are sent off-site on a
weekly basis to a secure secondary location. The data center currently manages over 125 terabytes
of data.
Information systems are available 24/7/365 unless a scheduled maintenance period or mitigation of
an unexpected event is required. Critical systems availability has exceeded 99.9% for the past 5
years.
7.2.3
Security, Support, Encryption, and Confidentiality
The data center coordinates the network infrastructure and security with University Information
Technology (UIT) at the University of Utah. This provides us with robust firewall hardware,
automatic network intrusion detection, and the expertise of dedicated security experts working at
the University. Centralized authentication and communication over public networks are encrypted
using transport layer security (TLS) and/or virtual private network (VPN) technologies. Direct
access to data center machines is only available while on premise or via a VPN client.
All network traffic is monitored for intrusion attempts. Security scans are regularly run against data
center servers and IT staff are notified of intrusion alerts. Security is maintained with Windows
user/group domain-level security. Users are required to change their passwords every 90 days. All
files are protected at user/group levels and database security is handled in a similar manner with
group-level access to databases, tables, and views. Finally, all laptops used by faculty and staff in
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the DCC are whole-disk encrypted.
The data center uses monitoring tools to continuously monitor applications and servers. Environ-
mental and network systems are also monitored to ensure up-time. System Administrators are
on-call 24/7/365 to respond to urgent events.
All personnel involved with the DCC have signed confidentiality agreements concerning data
encountered in the course of their daily work. All personnel (including administrative staff) have
received Human Subjects Protection and Health Information Portability and Accountability Act
education. We require all users to sign specific agreements concerning security, confidentiality, and
use of our information systems before access is provided.
7.3
Electronic Data Capture System
The Data Coordinating Center (DCC) will develop an electronic data capture system for this study.
Data will be entered by each clinical site, and data quality will be monitored at the DCC. The DCC
will use an electronic discrepancy management system to notify sites of inconsistent or erroneous
data entry, which will be corrected by the clinical site. The discrepancy management system
maintains an audit trail of all discrepancy resolution.
8
Study Site 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 PECARN studies, and we will utilize this process to ensure excellent quality data in
the proposed study. The DCC 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.
8.1
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
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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.
8.2
Clinical Site Monitoring
Site monitoring visits may be conducted by a trained site monitor 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. Interim visits
will take place depending on grant budget, site enrollment, and compliance issues identified. The
site monitor will provide each site with a written report, and sites will be required to follow up on
any deficiencies.
8.3
Remote Monitoring
The DCC may supplement on-site monitoring with remote monitoring activities. Remote monitoring
involves detailed review of the data entered by the Clinical Center and consultations with the Clinical
Center 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 DCC 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.
8.4
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, for source
verification of study documentation. In addition, medical information and data generated by this
study must be available for inspection by representatives (when applicable) of the Food and Drug
Administration (FDA), NIH, other Federal funders or study sponsors, and the Institutional Review
Board (IRB) of record (single IRB at the University of Utah). The investigative team will provide
a summary of the efforts made to contact the parent, guardian, legally authorized representative
and/or adult family members of the enrolled patients to the IRB at the time of continuing review.
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9
Protection of Human Subjects
9.1
Risks to Human Subjects
9.1.1
Potential Risks of Patient Participation
This study involves more than minimal risk, since the intervention involves administration of a
benzodiazepine, which has risk for respiratory depression. The intervention is a treatment for
seizures, so there is risk that inadequately treated seizures will contribute to ongoing seizures,
which could lead to brain damage and death. Since benzodiazepines are the standard of care for
treatment of seizures in the EMS setting, the only alternatives are to vary the dose and the route of
administration. Based on our prior work and other published literature, we believe that the proposed
routes and doses that will be utilized in the intervention are the safest options for the study subjects.
We anticipate that there will not be an increased rate of adverse effects from our proposed standard-
ized midazolam dosing relative to conventional dosing. Currently 50% of the participating EMS
affiliates allow 10 mg of midazolam as a maximum dose for the IM/IN routes. In addition, this dose
is similar to the standardized dosing used in the RAMPART trial.32 In that study, 14% of patients
required intubation, and there was no difference between those that received IM midazolam and
those that received IV lorazepam. This is also similar to data from our preliminary studies on this
topic.29, 31 Thus, the proposed standardized dosing regimen is unlikely to increase respiratory failure
risk relative to current practice.
There is minimal risk of potential loss of privacy and/or confidentiality, since personal identifiers
will be gathered.
There are no psychological, social, cultural, financial or legal risks to the patient that are expected
with standardized midazolam dosing relative to conventional midazolam dosing. There is a potential
differential risk for ongoing seizures, recurrent seizures, hypoxia, and/or respiratory depression with
one intervention relative to the other, though equipoise exists and is the premise for establishing
these as the primary and secondary outcomes that are being evaluated for this study. This study
involves no cost to the pediatric patients or their families. This study involves no cost to the EMS
providers.
9.1.2
Potential Risks to EMS Providers
For the EMS providers, demographic information such as the EMS provider’s years of experience,
years of employment with the EMS system, and age will be collected to describe those who
provided care to the study participants for subsequent peer-reviewed publication. Identifying
information about individual providers will not be shared with anyone except study personnel, and
their employers will not have access to study-related information about the care that the paramedics
provided. Once again, secure data transfer and storage measures, as noted above, will be utilized for
the EMS provider data. Information about the EMS providers, and all analyzed data, will be housed
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at the University of Utah Data Coordinating Center.
9.2
Adequacy of Protection Against Risks
9.2.1
Exception from Informed Consent (EFIC)
Administration of midazolam via the conventional and standardized protocols requires EFIC, since
prehospital seizures are a potentially life-threatening, time-critical condition for which the standard
of care is unsatisfactory, obtaining consent in the therapeutic window is not feasible, and there is a
prospect of direct benefit for enrolled children. Although it is highly unlikely to be feasible, the
investigators commit to: 1) Attempt to contact a parent, guardian, legally authorized representative,
or adult family member for each patient within the therapeutic time window, if feasible, and ask for
consent and 2) Contact an adult family member within the therapeutic time window, if feasible, to
ask whether the family member objects to the patient’s participation. This will be accomplished by
having the paramedic give the parent, guardian, legally authorized representative, or adult family
member a phone number that will be accessible 24 hours per day, 7 days per week. At the time
a parent/guardian phone call is received, the research staff will provide the study information
contained in the parental notification form, answer questions about the study, and obtain verbal
consent or objections to ongoing participation in the study, including the placement of the RR-EEG.
If the parent, guardian, legally authorized representative, or other adult family member expresses a
desire to discontinue participation, the date and time of objection will be noted, and the research staff
will immediately stop all trial interventions and data collection. They will specifically communicate
with the clinical staff in the affiliated ED to not place the RR-EEG, if it has not yet been placed,
or to remove the RR-EEG, if it is already in place. If obtaining informed consent from the parent,
guardian, or legally authorized representative is not feasible during the therapeutic time window
and/or an adult family member cannot be reached during the therapeutic time window to object
to trial participation, the research staff will, at the earliest feasible opportunity, inform the parent,
guardian, legally authorized representative or adult family member about the patient’s enrollment in
the trial, provide details about the trial included in the parental notification/informed consent form,
and inform the parent, guardian, legally authorized representative or adult family member that they
may discontinue trial participation at any time. The patient will also be informed as soon as feasible
and assent for continued trial participation will be obtained as appropriate.
The intervention is a system-wide implementation of a new protocol that will be applied to all
patients transported by a participating EMS agency, so there is not an alternative option for the
individual patient or the legally authorized representative.
The PediDOSE study meets the criteria for EFIC specified in FDA Regulation 21 CFR §50.24 for
the following reasons:
• The human subjects are in a life-threatening situation that necessitates urgent intervention;
– Ongoing seizures are life-threatening because they lead to respiratory depression, brain
damage, and death.
• The therapeutic time window for treatment of convulsive status epilepticus with benzodi-
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azepine medication is 0–5 minutes;1
• Available treatments are unproven or unsatisfactory;
– Currently 1/3 of these patients arrive at EDs still having a seizure, so conventional
treatment and dosing is unsatisfactory.
• Collection of valid scientific evidence is necessary to determine the safety and effectiveness
of the intervention;
– It is unknown if standardized dosing is more (or less) effective than conventional dosing,
and the impact on safety is unknown.
• Obtaining informed consent prior to seizure management in the field is not feasible because
the therapeutic window is too short and many pediatric seizures in EMS are new-onset in
nature, making it impossible to predict in advance who will be eligible for the study;
– The on-scene paramedic(s) will be focused on high priority patient care steps (e.g.,
patient assessment, intervening for respiratory distress, determination of the midazo-
lam dose required to stop the seizure, drawing up the medication for administration,
reassessing the patient);
– Parents/guardians may be absent; if they are present, they are often in distress when
their child is having a seizure.
• The intervention must be administered before consent can be obtained;
– Since untreated seizures can lead to self-sustaining status epilepticus,23, 34 it is imperative
that treatment is not delayed.
• There is no reasonable way to identify prospectively individuals likely to become eligible for
participation;
– Many children who have a seizure in the EMS setting experience it for the first time in
their lives, making prospective identification impossible.
• Participation in the research holds out the prospect of direct benefit to the subjects;
– Since prior research demonstrates that midazolam 0.2 mg/kg given IN or IM is effica-
cious at stopping seizures, participation in this research study in which the intervention
is focused on optimizing delivery of midazolam at this dose and via one of these routes
does hold the prospect of direct benefit to the subjects.
• The clinical investigation could not practicably be carried out without the waiver.
Therapeutic Time Window.
Kaplan-Meier curves from an EMS-based study demonstrate the
biggest reduction in duration of status epilepticus in patients treated in the first 0–5 minutes.1
Another EMS-based study of status epilepticus showed that among subjects whose seizures ceased
before arrival to the emergency department(ED), the median time to active treatment was <5
minutes.32 Specifically in pediatrics, treatment delays in seizures lasting more than 5 minutes are
associated with prolonged status epilepticus,9 such that many hospital-based guidelines specifically
recommend the administration of first-line benzodiazepine treatment within 5 minutes.35 This is also
consistent with Canadian guidelines on the emergency management of convulsive status epilepticus
in pediatric patients, which allows for 5 minutes to establish that a seizure warrants treatment, 5
minutes for the first benzodiazepine dose to be administered, and another 5 minutes for a second
benzodiazepine dose to be administered for ongoing seizures.24
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Community Consultation.
Each site will prepare a community consultation plan, will submit
that plan to the University of Utah IRB for approval, will execute the community consultation,
and will provide the results of that consultation to the Utah IRB for approval by the IRB. The
community consultation plans will include public disclosures, opportunities to obtain information
about the study, informational materials for distribution, and local input from the community using
an anonymous survey and semi-structured interviews with members of the community, including
parents or guardians of children in the eligible age range for the study. These strategies will also
be used to gather feedback from paramedics in these communities. As part of the community
consultation process, the public will also be informed about the options they will have to object
to further participation in the trial if an ambulance is called for a seizure in a pediatric family
member. Each site will have its own individualized consultation plan to meet the needs of its specific
community. Large, open public forums will likely not be planned, since the COVID-19 pandemic is
still ongoing and community participation in such events may be unsafe for the public. Furthermore,
such forums have had limited success in previous PECARN network studies requiring EFIC.4, 5, 18, 27
9.2.2
Opt Out, Notification, and Withdrawal
Opt-out.
Since EMS medical directors will change EMS agency protocols to standardize and
ensure safe care, individuals cannot meaningfully opt out of the study intervention itself, which is
the revised EMS seizure protocol that utilizes age-based midazolam dosing. However, paramedics
will be informed about options available to participants to object to the collection of study data and
will be provided with a contact phone number that can be given to parents in the event there is an
opportunity for research staff to discuss study information with the parent/guardian/other in the
pre-hospital environment. If the adult in attendance with the child at the time of enrollment tells the
paramedic that they object to participation in the trial, the paramedic will convey that information to
the research staff after arrival to the ED as well as the date/time of the objection. This information
will be collected as a part of the paramedic self-report, so that study-related data collection is halted
from the date/time that the paramedic received notification of the objection.
Since this is a study involving only children, the research coordinator (RC) at each site will notify
the parent or guardian of the child and specific study patients (defined on the following page)
about enrollment in the study at the earliest feasible opportunity. This notification will involve a
description about the study, including a notification form describing options for continued study
participation. This form provides options for ongoing participation. These options are:
1. I agree to continued participation in the study, including data collection regarding care that
my child receives until he/she is discharged from the hospital
2. I object to continued participation in the study, including no further trial interventions, the
use of the rapid response encephalogram (RR-EEG), and no additional data collection
3. I object to continued participation in the study including no further trial interventions, but
allow ongoing/additional data collection
If the RC cannot successfully notify the parent, guardian, legally authorized representative in-
person or via phone, then the RC will notify another adult family member or responsible adult in
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attendance with the child. If no one is in attendance with the child or if the child has already been
discharged before the RC can make in-person contact in the hospital, the RC will attempt to notify
the parent/guardian via phone. If that is unsuccessful, the RC will notify the parent/guardian via
mail.
The majority of the children having a seizure in each of the participating metropolitan areas are
transported to children’s hospital EDs that are affiliated with the study and that have RC staffing.
Since there are numerous other EDs in each of these metropolitan areas, most of these EDs do
not have any RC staffing, and the number of RCs required to staff all of these EDs would likely
exceed the number of potentially eligible patients who could be enrolled at these other EDs, it is
not practicable to provide in-person notification in situations when the patient is transported to
these non-affiliated EDs. Therefore, RCs will make attempts to notify the parent/guardian of these
patients by phone and will then notify by mail if phone contact is unsuccessful.
Earliest Feasible Opportunity.
The earliest feasible opportunity for notification of study enroll-
ment occurs in the Emergency Department and research staff will work closely with hospital staff to
ensure the parents are notified at the earlies opportunity.
At the earliest feasible opportunity to communicate with the patient, the RC will also give an
opportunity for certain minors to object to further participation if they are:
1. 7–13 years old and
2. Have the developmental ability to communicate and
3. Do not have a baseline significant cognitive impairment noted in their medical record that
would impair their ability to comprehend information about the trial
Patients who are 6 months to 6 years old will not be informed about the trial, since they have not
yet attained the appropriate cognitive development to comprehend information about the trial.
If the earliest feasible opportunity occurs when a RC is not present in the hospital, typically in
the middle of the night, clinical staff at affiliated hospitals may provide the parent with written
information and a phone number where questions can be answered. If the patient is transported to a
non-affiliated ED where no study-affiliated RC is present at all, the RC will make attempts to notify
a parent/guardian by phone at the earliest feasible opportunity. If attempts to contact by phone are
unsuccessful, the RC will send appropriate notification forms via mail and/or email.
In the event that the research subject dies before notification occurs, the research staff will send a
letter to the parent/guardian 1–2 weeks after the subject dies. The reason for waiting at least 1 week
is that the family will be too distraught to process this information soon after the death occurred.
Withdrawn Participants.
Once notification of objection is received by the study team, no further
data collection or study interventions, including use of the RR–EEG will be attempted in accordance
with the option selected at the time of signature or verbal notification. As per the FDA guidance
regarding withdrawn participants, data that has already been collected will be retained in sufficient
manner to maintain adequate case histories recording all observations and other pertinent data to
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the investigation on each individual treated with the investigational product.
Public Disclosure of Trial Results.
The investigators will disclose information about the study’s
procedures, risks, and benefits prior to initiation of the study (as part of community consultation)
and will publicly disclose the study findings after completion. This disclosure may occur through
television and radio public service announcements, newspaper articles, posted flyers in pediatric
EDs, pediatric neurology clinics, and general pediatrics offices, via the study website, and/or through
presentations to professional organizations. Physically posted and mailed information will be in
English and Spanish.
9.2.3
Collection of Mortality and Outcome Data on All Eligible Subjects
Since the unit of randomization is the EMS agency, failure to collect outcome and safety data on all
patients treated with the EMS seizure protocol and transported to the study hospitals would lead to
incomplete and potentially biased data collection that would inaccurately assess the effectiveness
and safety of the system-wide protocol implementation. Patients who meet the following criteria
are considered to be research subjects in this study:
1. Ages 6 months to 13 years old and
2. Have an active seizure in the presence of a paramedic in one of the EMS agencies participating
in the study
Since all of these patients are either in the intervention (treated under the revised EMS seizure
protocol) or control group (treated under the existing EMS seizure protocol), all of the patients who
meet the above noted criteria will be enrolled in the study under EFIC. The scientific validity of the
study is dependent on capturing all eligible patients during the study period, as one of the major
goals is to accurately describe the characteristics of the entire eligible population.
Since all patients who meet the above-noted criteria will be exposed to either the intervention or the
comparison, the investigators will attempt to do all of the following with parents, guardians, legally
authorized representatives, or another adult family member of patients who meet the above-noted
criteria: 1) Obtain informed consent, if feasible, as noted in Section 9.2.1 on page 28; 2) Notify
them within the therapeutic time window as noted in Section 9.2.2 on page 30; and 3) Provide
notification to them at the earliest feasible opportunity as noted in Sections 9.2.1 on page 28 and
9.2.2 on page 30; and 4) Provide an opportunity to object to further data collection as noted in
Sections 9.2.1 on page 28 and 9.2.2 on page 30.
Since it is important to ensure that there is no discrepancy in safety between patients transported to
the affiliated EDs and those who are taken to other non-affiliated EDs, it is scientifically essential to
acquire data on mortality for all patients involved in the study. In addition, we plan to collect data
on the primary outcome (having a seizure on ED arrival) based on the paramedic self-report and
documentation in the EMS record, as long as the paramedic has not been notified of any objection to
collection of this information and the research staff has made their best efforts to provide notification.
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This study utilizes a stepped-wedge design, and the patients who are being treated under the EMS
agency’s existing seizure protocol (prior to randomization to implement the intervention—the
standardized seizure protocol) are enrolled in the control group. Since comparing the intervention
group to the control group is essential to the scientific design of the trial, we will collect data on
patients in the control group who are transported by the participating EMS agency. For patients
between 6 months and 23 months old, they will receive care under the EMS agency’s existing
conventional dosing seizure protocol until the Data Safety Monitoring Board (DSMB) deems that it
is safe to lower the age for standardized dosing. These patients will be enrolled in the control group
until that happens. Since comparing the intervention group to the control group is essential to the
scientific design of the trial, data will be collected for these control group patients until the DSMB
deems that it is safe to make them part of the intervention group.
9.2.4
Vulnerable Subjects
Vulnerable populations in this study are children, including Wards of the State, and employees of
EMS agencies. Children will be included because this is a study that focuses on improving pediatric
seizure management in EMS. Wards of the State are included in the study because there is no way
to exclude participants who receive EMS treatment based on custody status. The rationale for
including children in a study like this is that children as a whole receive care that is not equitable
relative to adults in the EMS setting, and pediatric seizures in EMS have been identified as a high
priority area of research due to their frequency and the gaps in knowledge that exist.2, 10, 17 There
is no undue coercion since care received in the prehospital setting and the emergency department
will be administered according to existing patient care protocols/guidelines. Research in children
involves special protections under 45 CFR §46 Subpart D “Additional DHHS protections for
children involved as subjects in research” and 21 CFR §50 and §56. The study in this protocol is
permissible under these regulations as:
• Research involving greater than minimal risk but presenting the prospect of direct benefit to
the individual subjects (45 CFR §46.405).
Wards of the State enrolled in this study will be afforded additional protections according to
regulations enforced by the University of Utah SIRB and local policies and guidelines enforced by
the relying HRP. These protections will include documentation of consent from the legal guardian
and withdrawal of data in the event the legal guardian is unavailable for consent. Additional
protections may be implemented at individual sites if these requirements do not satisfy local
requirements.
EMS providers are potentially vulnerable because data will be collected that could potentially
identify individual practice patterns for paramedics administering care under this protocol. This
risk is mitigated by the employment of confidentiality practices. Identifying information about
individual providers will not be shared with anyone except study personnel, and their employers
will not have access to study-related information about the care that the paramedics provided.
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9.2.5
Institutional Review Board and Human Research Protection
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.
9.2.6
Protections Against Risk
Expertise of providers.
Children eligible for this study are cared for by expert pre-hospital
paramedic staff, and are taken to emergency departments that are staffed by qualified pediatric
emergency physicians , nurses and respiratory therapists. Subjects are evaluated continuously in the
emergency setting, and all centers are well prepared to evaluate and treat any complications that can
arise from participation in the study.
Loss of Confidentiality
The minimal risk of loss of privacy is mitigated by the substantial data
management resources and security described in Section 7.2.3 on page 24.
9.3
Potential Benefits of Proposed Research
Potential benefits for subjects who are treated with standardized, age-based midazolam dosing
include: few medication dosing errors, faster resolution of their seizure, less respiratory failure, and
decreased length of hospital stay. These benefits are theoretical, since clinical equipoise exists and
it is unknown if standardized, age-based midazolam dosing is better than conventional dosing with
respect to these outcomes. The results of this study will give valuable feedback to the EMS system
regarding prehospital seizure treatment for pediatric patients. The information from this study could
be used to improve the care of children in the prehospital setting. The anticipated benefit to society
in understanding how to optimally dose seizure medication for children in the prehospital setting
outweighs the minimal risk of loss of confidentiality.
9.4
Importance of the Knowledge to be Gained
The importance of the knowledge to be gained from this study is that current treatment of pediatric
seizures in EMS has a high failure rate, but doing this study will demonstrate if utilizing age–based,
standardized midazolam dosing improves outcomes. If outcomes are improved, the findings from
this study could be easily translated into practice in numerous EMS agencies across the country.
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Thus, this study has the potential to positively impact the management of pediatric seizures on a
national level. If this study demonstrates that standardized age-based dosing is more effective than
conventional dosing, it will shift the paradigm in EMS management of pediatric seizures across the
country.
10
Data and Safety Monitoring Plan
10.1
Data Safety Monitoring Board (DSMB)
The study will have a Data Safety Monitoring Board (DSMB) composed of individuals independent
of the study. Members will have expertise in statistics, medical ethics, emergency medical services,
pediatric emergency medicine, and/or neurology. The DSMB will have a charter, will approve the
protocol prior to implementation, and will review interim data as applicable. The purpose of the
DSMB is to advise the 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 agency and site, review of adverse events, and other subject safety issues.
10.2
Adverse Event Reporting
Adverse events occurring in the field or hospital will be recorded for eligible subjects, up to the time
of ED discharge, hospital discharge, or 12 hours after ED arrival, whichever is earliest.
10.2.1
Definition of Adverse Event and Serious Adverse Event
Adverse Event (AE).
An adverse event means any untoward medical occurrence associated with
the use of an intervention in humans, whether or not considered intervention-related (21 CFR
§312.32 (a)). An event constitutes a disease, a set of related signs or symptoms, or a single sign or
symptom.
Serious Adverse Event (SAE).
A serious adverse event (SAE) for this population is an adverse
event that:
• results in death; or
• is life-threatening (immediate danger of death from the event as it occurred); or
• requires new inpatient hospitalization or prolongs an existing hospitalization; or
• results in persistent or significant disability or incapacity; or
• results in congenital anomaly/birth defect; or
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• 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.
10.2.2
Classification of Adverse Events (Relatedness and Expectedness
Clinical judgment is required for properly classifying relatedness and expectedness for adverse
events. It is not appropriate to classify an event as possibly related if, in the opinion of the clinical
investigator, it is clinically unlikely that the event is related. It is impossible to prove a negative,
and the FDA expects clinical judgment to be used in assessing relatedness. Similarly, it is not
appropriate to classify an event as unexpected because the patient was not anticipated to suffer the
event at the time of enrollment into the study, if the event is a known sequelae of the underlying
disease process or has been previously noted with midazolam administration.
Relatedness:
The suspected relationship between midazolam administration and any adverse
event 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 believed to be 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 a clinically compatible temporal sequence from the time of
administration of midazolam, 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 midazolam
administration, and cannot be reasonably explained by other factors such as the subject’s
clinical state, therapeutic interventions, or concomitant drugs administered to the subject.
Expectedness of the Event:
All adverse events, including serious adverse events, will be evaluated
as to whether their occurrence was expected or unexpected. An AE will be considered unexpected
if the nature, severity, or frequency of the event is not consistent with complications of seizures,
existing conditions for the patient, nor consistent with adverse events noted from midazolam
administration.
Expected: An event is considered expected if it is known to be associated with the underlying
condition or is related to midazolam administration. An event may be expected despite the
study subject’s clinical state immediately prior to the event.
Unexpected: An event is considered unexpected if there are no prior data linking this event with
either the patient’s condition or administration of midazolam.
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Adverse events that are expected from the intervention include dizziness, hiccups, and nystagmus.
Additional adverse events that will be closely monitored are the presence of anterograde amnesia,
nausea, vomiting, hypoglycemia, headache, syncope, abnormal movements (tremors/twitches not
due to a seizure), agitation, cellulitis or abscess at the IM injection site, rash at the IM injection
site, hematoma at the IM injection site, epistaxis, or hypothermia (temperature <35◦C). We do
not anticipate an increased risk of these complications by giving midazolam using standardized,
age-based dosing relative to conventional dosing.
We plan to monitor for these as well as the following critical adverse events, which are safety events
of special interest:
• Life threatening hypotension unresponsive to 20 ml/kg fluid bolus: systolic blood pressure
remaining below age-specified thresholds in mm Hg:
– 6–11 months: < 60
– 1–10 years: < [(age in years) x 2] + 70
– >11 years: < 90
• Life threatening cardiac arrhythmia requiring intervention with chest compressions, pacing,
defibrillation, or the use of an anti-arrhythmic agent or procedure;
• Respiratory failure in the prehospital setting or within 30 minutes of ED arrival, requiring
bag valve mask (BVM) ventilation, bi-level positive airway pressure (BiPAP), continuous
positive airway pressure (CPAP), or placement of a supraglottic airway (SGA) or endotracheal
intubation (ETI);
• Depressed level of consciousness defined as Glasgow Coma Score <8 that persists more than
4 hours after ED arrival.
Treatment or Action Taken:
For each adverse event, the site investigator will record whether an
intervention 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 adverse
event as follows:
• Death
• Recovered and the patient returned to baseline status
• Recovered with sequelae
• Symptoms persist
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10.2.3
Data Collection Procedures for Adverse Events
All adverse events (including serious adverse events) in the reporting window will be recorded
according to relatedness, severity, and expectedness, as well as their duration and any treatment
prescribed.
Adverse events will be coded using the MedDRA coding vocabulary. Coding will be done centrally
at the Data Coordinating Center.
10.2.4
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 report these unanticipated problems to the NINDS Project Officer in an expedited manner (as
close to 24 hours as possible). The medical monitor (Section 10.2.5) for the study will assess the
report, and reporting to the University of Utah IRB, acting as the single IRB for the study, may
be required. In addition, dependent on the nature of the unanticipated problem, all participating
institutions may require notification. In the event that the medical monitor believes that such an
event warrants emergent suspension of enrollment in the trial, and NINDS staff cannot be reached
expeditiously, the Data Coordinating Center will notify the study investigators (Dr. Shah ) and all
site investigators to cease enrollment in the trial. Resumption of enrollment will not occur without
consent of the NINDS staff after discussion with the DSMB.
10.2.5
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.
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 NINDS staff. The SAE reporting process may be incorporated into the Electronic Data Capture
(EDC) System in use for the study.
In the unlikely event that the medical monitor believes an unexpected and study-related SAE war-
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rants emergent cessation of enrollment in the trial, NINDS staff and the DSMB chairperson will be
immediately consulted. If these individuals concur with the judgment of the medical monitor, or if
the NINDS staff and the DSMB chairperson cannot be reached expeditiously, the Data Coordinating
Center will notify the study investigators (Dr. Shah ) and all site investigators to cease enrollment
in the trial. Resumption of enrollment will not occur without consent of the NINDS staff after
discussion with the DSMB. The sIRB in Utah will be notified, and each site investigator will notify
their institutional Human Research Protection program of the trial suspension.
After notification of the NINDS 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 investigators (Dr. Shah) and all clinical investigators, who will be instructed to
report this to their institutional Human Research Protection program.
The DSMB will review all adverse events (not necessarily serious, unexpected, and study-related)
during scheduled DSMB meetings. The Data Coordinating Center will prepare a Summary Report
of Adverse Events for the DSMB meetings, classified with the MedDRA coding system.
10.2.6
Follow-up of Serious, Unexpected and Related Adverse Events
All serious, unexpected and related adverse events, that are unresolved at the time of the patient’s
termination from the study or discharge from the affiliated hospital, will be followed by the site
investigators until the events are resolved, subject is lost to follow-up, the adverse event is otherwise
explained or has stabilized, and continuity of care with a responsible clinical team has been assured.
10.2.7
Reporting to the Food and Drug Administration
Serious, unexpected and related adverse events will be reported to the FDA in an expedited manner
consistent with FDA requirements. The Data Coordinating Center will prepare the report for
submission by the principal investigator, Dr. Shah, who will hold the IND.
11
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 subset of research and/or clinical staff will also receive training on the RR-EEG device
directly from the device manufacturer’s representative, so that they can train other relevant site staff
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on the proper storage, application, use, and disposal of the device. No site will be activated until all
training requirements have been fulfilled by the site investigators and research staff.
A manual of operations will be provided to each investigator prior to the start of enrollment. 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 PI (Dr.
Shah), will be the main contact for study questions.
All paramedics in the participating EMS agencies will be informed about the details of the study
before any patient enrollment begins, so that they are aware of the study and know how to notify
research staff at the hospital if an adult family member of the patient informs them of their desire
not to have the patient’s data utilized for the study. In addition, mandatory in-person training of
EMS providers, will occur once for each paramedic in a given EMS system and begin no earlier
than 4 months prior to implementation of the standardized protocol. The number of trainings in
each EMS system will be determined based on EMS system logistics to ensure that all providers
can attend the training once. When the new standardized dosing protocol is implemented, all adults
and children will be treated with the protocol because the EMS agencies have agreed to change their
system-wide seizure protocol for the study. Standardization of the protocol is necessary to avoid
confusion among paramedics when treating patients in the field.
12
Regulatory Considerations
12.1
Food and Drug Administration
While midazolam is approved for use in pediatric patients by the FDA, and there are several FDA
approved EEG recording devices that can be used in children, this study is being done under
Exception from Informed Consent (EFIC). For that reason, an IND has been submitted to cover the
drug (IND 156119).
The FDA has determined that an IDE is not required for this trial, since this study will not investigate
a new or modified use of the RR-EEG device, nor will safety or effectiveness data for the device
be collected. No site is required to use the RR-EEG device for clinical decision-making. If a site
chooses to use the RR-EEG device as an adjunct to clinical decision-making, they will be advised
of the age-specific FDA approval for different features of the device.
All IRB-approved community consultation and public disclosure materials will be submitted to the
FDA and to Public Docket number 95S-0158.
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12.2
Health Insurance Portability and Accountability Act
Data elements collected include the date of birth and date of admission. Prior to statistical analyses,
dates will be used to calculate patient age at the time of the study events.
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 DCC handling potential protected health information (PHI) 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 DCC.
12.3
Inclusion of Women and Minorities
There will be no exclusion of patients based on gender, race, or ethnicity.
12.4
Clinical Trial Registration Requirements
The PediDOSE trial is registered at https://clinicaltrials.gov in accordance with Federal
regulations (ClinicalTrials.gov ID: NCT05121324).
12.5
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)].
12.6
Public Use Data Set
After subject enrollment and follow up have been completed, the DCC 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
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any institutional identifiers.
The DCC 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.
13
Bibliography
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16(1):59–66, 2012.
[16] J. D. Hoyle, Jr, R. P. Crowe, M. A. Bentley, G. Beltran, and W. Fales. Pediatric prehospital
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[17] Institute of Medicine. Emergency Medical Services: At the Crossroads. National Academies
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C. Meinzer, H. Cock, N. Fountain, J. T. Connor, R. Silbergleit, and NETT and PECARN
Investigators. Randomized trial of three anticonvulsant medications for status epilepticus. N
Engl J Med, 381(22):2103–2113, 11 2019.
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pediatric emergency. Acad Emerg Med, 19(1):37–47, Jan 2012.
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during a simulated, prehospital, pediatric cardiopulmonary arrest. Simul Healthc, 9(3):174–83,
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[21] E. S. Lang, D. W. Spaite, Z. J. Oliver, C. S. Gotschall, R. A. Swor, D. E. Dawson, and
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guidelines for prehospital care. Acad Emerg Med, 19(2):201–9, Feb 2012.
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21(12):1430–4, Dec 1992.
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patient with convulsive status epilepticus. Paediatrics & child health, 26:50–66, Feb. 2021.
[25] A. McTague, T. Martland, and R. Appleton. Drug management for acute tonic-clonic con-
vulsions including convulsive status epilepticus in children. Cochrane Database Syst Rev,
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[26] National Association of State EMS Officials. 2020 National EMS Assessment.
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S. E. Barnhard, M. Bobinski, S. Ghetti, J. F. Holmes, I. Roberts, W. O. Schalick, 3rd, N. K.
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the Pediatric Emergency Care Applied Research Network. Traumatic injury clinical trial
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controlled trial. Trials, 19(1):593, Oct 2018.
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Camp, S. J. Prater, and C. B. Doughty. Impact of high-fidelity pediatric simulation on
paramedic seizure management. Prehosp Emerg Care, 20(4):499–507, 2016.
[30] M. I. Shah, C. G. Macias, P. S. Dayan, T. S. Weik, K. M. Brown, S. M. Fuchs, M. E. Fallat,
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management using grade methodology. Prehosp Emerg Care, 18 Suppl 1:15–24, 2014.
[31] M. I. Shah, D. G. Ostermayer, L. R. Browne, J. R. Studnek, J. M. Carey, C. Stanford, N. Fumo,
and E. B. Lerner. Multicenter evaluation of prehospital seizure management in children.
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[32] R. Silbergleit, V. Durkalski, D. Lowenstein, R. Conwit, A. Pancioli, Y. Palesch, W. Barsan,
and NETT Investigators. Intramuscular versus intravenous therapy for prehospital status
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delivery and dosing errors in simulated prehospital pediatric resuscitations: A randomized
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[34] S. K. H. Tay, L. J. Hirsch, L. Leary, N. Jette, J. Wittman, and C. I. Akman. Nonconvulsive
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Hospital emergency treatment of convulsive status epilepticus: Comparison of pathways from
ten pediatric research centers. Pediatric neurology, 86:33–41, Sept. 2018.
[36] J. W. Wheless. Treatment of status epilepticus in children. Pediatr Ann, 33(6):376–83, Jun
2004.
PediDOSE Protocol Version 1.04
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Statistical Analysis Plan
Protocol Title (Number): Pediatric Dose Optimization for Seizures in EMS (052)
Protocol Version and Date: 1.04; June 3, 2022
SAP Author: John M. VanBuren, Ph.D.
SAP Version and Date: 1.00; July 20, 2022
SAP Version 1 Date: July 20, 2022
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Approvals:
Approved By:
Name
Title
Date
Name
Title
Date
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Contents
Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
vi
1
PREFACE
1
1.1
Purpose of SAP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.2
Auxiliary/Other Documents . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
2
STUDY OBJECTIVES AND OUTCOMES
1
2.1
Study Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
2.1.1
Primary Objective
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
2.1.2
Secondary Objective . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
2.2
Study Outcomes
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
2.2.1
Primary Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
2.2.2
Secondary Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
2.2.3
Tertiary Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
2.2.4
Safety Outcomes
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
3
STUDY DESIGN AND METHODS
3
3.1
Overall Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3
3.1.1
Age De-Escalation
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
3
3.2
Method of Treatment Assignment and Randomization . . . . . . . . . . . . .
3
3.2.1
Delivery of Randomization . . . . . . . . . . . . . . . . . . . . . . . .
5
3.2.2
Handling of Incorrect Randomization in Study Analyses and Reports
5
3.3
Treatment Masking (Blinding) . . . . . . . . . . . . . . . . . . . . . . . . . .
5
4
STUDY SUBJECTS AND ANALYSIS POPULATIONS
5
4.1
Eligibility
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5
4.2
Populations for Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5
4.2.1
Screening Population . . . . . . . . . . . . . . . . . . . . . . . . . . .
5
4.2.2
Eligible/Enrolled Population . . . . . . . . . . . . . . . . . . . . . . .
6
4.2.3
Statistical Analysis Population
. . . . . . . . . . . . . . . . . . . . .
6
4.2.4
Intention-to-Treat Population . . . . . . . . . . . . . . . . . . . . . .
6
4.2.5
As-Treated Population . . . . . . . . . . . . . . . . . . . . . . . . . .
7
4.2.6
Per-Protocol Population . . . . . . . . . . . . . . . . . . . . . . . . .
8
4.2.7
Midazolam Population . . . . . . . . . . . . . . . . . . . . . . . . . .
8
4.2.8
Safety Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
4.2.9
Visual Representation of Populations . . . . . . . . . . . . . . . . . .
8
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5
GENERAL ISSUES FOR STATISTICAL ANALYSES
9
5.1
Analysis Software . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
5.2
Methods for Withdrawals, Missing Data, and Outliers . . . . . . . . . . . . .
9
5.3
Multiple Comparisons and Multiplicity . . . . . . . . . . . . . . . . . . . . .
10
5.4
Planned Subgroups, Interactions, and Covariates . . . . . . . . . . . . . . . .
10
5.5
Derived and Computed Variables
. . . . . . . . . . . . . . . . . . . . . . . .
11
5.5.1
Data Used in Analyses . . . . . . . . . . . . . . . . . . . . . . . . . .
11
5.5.2
Ceribell Seizures
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
5.5.3
Seizing on ED Arrival
. . . . . . . . . . . . . . . . . . . . . . . . . .
12
5.5.4
Respiratory Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
5.5.5
Time to First Midazolam Administration . . . . . . . . . . . . . . . .
14
5.5.6
Time to Seizure Cessation in ED
. . . . . . . . . . . . . . . . . . . .
14
5.5.7
Dose/Route Adherence . . . . . . . . . . . . . . . . . . . . . . . . . .
14
5.5.8
Life Threatening Hypotension . . . . . . . . . . . . . . . . . . . . . .
15
5.5.9
Life Threatening Cardiac Arrhythmia . . . . . . . . . . . . . . . . . .
15
5.5.10 Depressed Level of Consciousness . . . . . . . . . . . . . . . . . . . .
15
5.5.11 Method of Dose Determination
. . . . . . . . . . . . . . . . . . . . .
16
5.5.12 Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
5.5.13 Prior History of Seizure
. . . . . . . . . . . . . . . . . . . . . . . . .
16
5.5.14 Receipt of Bystander-Administered Benzodiazepine . . . . . . . . . .
16
5.5.15 Route of Midazolam Administration
. . . . . . . . . . . . . . . . . .
16
5.5.16 Time (months) since study start . . . . . . . . . . . . . . . . . . . . .
16
5.5.17 Age
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
5.5.18 Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
5.6
Independent Review
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
6
INTERIM ANALYSES
17
6.1
Frequency of and Timepoints for Interim Analysis . . . . . . . . . . . . . . .
17
6.2
Stopping Rules for Interim Eﬃcacy Analysis . . . . . . . . . . . . . . . . . .
17
6.3
Blinding in the Interim Analysis . . . . . . . . . . . . . . . . . . . . . . . . .
18
7
PLANNED ANALYSES
18
7.1
Description of Subject Characteristics . . . . . . . . . . . . . . . . . . . . . .
18
7.2
Primary Outcome Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18
7.2.1
Additional Analyses of Primary Outcome . . . . . . . . . . . . . . . .
19
7.3
Secondary Outcome(s) Analyses . . . . . . . . . . . . . . . . . . . . . . . . .
19
7.3.1
Respiratory Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
7.3.2
Time to First Midazolam Administration . . . . . . . . . . . . . . . .
19
7.4
Tertiary Outcome(s) Analyses . . . . . . . . . . . . . . . . . . . . . . . . . .
20
7.4.1
Time to Seizure Cessation in ED
. . . . . . . . . . . . . . . . . . . .
20
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7.4.2
Dose/Route Adherence . . . . . . . . . . . . . . . . . . . . . . . . . .
20
7.5
Technical Approaches for Subgroup Analyses . . . . . . . . . . . . . . . . . .
20
7.6
Safety Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
7.6.1
Formal Safety Outcome(s) . . . . . . . . . . . . . . . . . . . . . . . .
20
7.6.2
Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
8
SAMPLE SIZE DETERMINATION
21
9
References
22
A INTERIM LOOK INFORMATION SPENDING
23
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Abbreviations
Abbreviation
Deﬁnition
AS-TREATED
As-Treated Population
BiPAP
Bi-level Positive Airway Pressure
BVM
Bag Valve Mask
CONSORT
Consolidated Standards of Reporting Trials
CPAP
Continuous Positive Airway Pressure
DCC
Data Coordinating Center
CPR
Cardiopulmonary Resuscitation
CRF
Case Report Form
DSMB
Data and Safety Monitoring Board
ED
Emergency Department
EEG
Electroencephalogram
EFIC
Exception From Informed Consent
EMS
Emergency Medical Services
ENROLLED
Eligible and enrolled population
ETT
Endotracheal Tube
GCS
Glasgow Coma Scale
IM
Intramuscular
IN
Intranasal
IO
Intraosseous
ITT
Intent-To-Treat Population
IV
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
MIDAZOLAM
Midazolam Population
PediDOSE
Pediatric Dose Optimization for Seizures in EMS
PP
Per-Protocol Population
PR
Rectal
(S)AE
(Serious) Adverse Event
SAFETY
Safety Population
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SCREEN
Screening Population
SGA
Supraglottic Airway
STAT POPULATION
Statistical Analysis Population
SW
Stepped Wedge
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1
PREFACE
1.1
Purpose of SAP
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for the
protocol: Pediatric Dose Optimization for Seizures in EMS (PediDOSE).
The structure and content of this SAP provides suﬃcient detail to meet the requirements
and standards set by the Data Coordinating Center (DCC).
1.2
Auxiliary/Other Documents
The following documents were reviewed in preparation of this SAP:
• Protocol: Pediatric Dose Optimization for Seizures in EMS.
• Case Report Forms (CRFs) for the PediDOSE protocol
The reader of this SAP is encouraged to read the protocol for details on the conduct of this
study, and the operational aspects of clinical assessments.
The purpose of this SAP is to outline the planned analyses to be completed for the Pedi-
DOSE trial. The planned analyses identiﬁed in this SAP will be included in future study
abstracts and manuscripts. Also, exploratory analyses not necessarily identiﬁed in this SAP
may be performed. Any post hoc, or unplanned, analyses not explicitly identiﬁed in this
SAP will be clearly identiﬁed as such in any published reports from this study.
It is possible that, due to updates or identiﬁcation of errors in speciﬁc statistical software
discussed in this SAP, the exact technical speciﬁcations for carrying out a given analysis may
be modiﬁed. This is considered acceptable as long as the original, prespeciﬁed statistical
analytic approach is completely followed in the revised technical speciﬁcations.
2
STUDY OBJECTIVES AND OUTCOMES
2.1
Study Objectives
2.1.1
Primary Objective
The primary objective of this study is to compare the impact of standardized EMS mida-
zolam dosing on seizure cessation. We hypothesize that standardized intramuscular (IM)
or intranasal (IN) midazolam dosing of approximately 0.2 mg/kg, based on age-based esti-
mates for weight, will be associated with lower frequency of active seizures upon Emergency
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Department (ED) arrival, when compared to conventional dosing with calculations from
estimated weights.
2.1.2
Secondary Objective
The secondary objective of this study is to compare the frequency of respiratory failure after
implementation of standardized Emergency Medical Services (EMS) midazolam dosing for
pediatric seizures. We hypothesize that standardized dosing will not increase respiratory
failure when compared to conventional dosing.
2.2
Study Outcomes
2.2.1
Primary Outcome
The primary outcome is the proportion of patients seizing on ED arrival.
2.2.2
Secondary Outcomes
The two secondary outcomes are:
• Proportion of patients with respiratory failure in the prehospital setting or within 30
minutes of ED arrival, deﬁned as having received bag valve mask (BVM) ventilation,
bi-level positive airway pressure (BiPAP), continuous positive airway pressure (CPAP)
or placement of a supraglottic airway (SGA) or endotracheal tube (ETT);
• Time to ﬁrst midazolam administration after paramedic arrival to the scene.
2.2.3
Tertiary Outcomes
Tertiary outcomes include:
• Time to seizure cessation in the ED, if still seizing on ED arrival;
• Dose/route adherence, deﬁned as receiving a midazolam dose within 30% of protocol-
ized dose
2.2.4
Safety Outcomes
Safety outcomes include:
• Life threatening hypotension
• Life threatening cardiac arrhythmia
• Depressed level of consciousness
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3
STUDY DESIGN AND METHODS
3.1
Overall Study Design
This study is a Phase 3, multi-center, stepped wedge trial of midazolam dosing for seizures
in pediatric patients in the EMS setting. It randomizes the timing of each of the partici-
pating EMS agencies at 20 diﬀerent sites to switch from conventional, weight-based dosing
to standardized, age-based dosing, so that every EMS agency switches from conventional to
standardized dosing over a 4-year enrollment period in this 5-year study. Federal exception
from informed consent (EFIC) procedures will be used for enrollment. PediDOSE utilizes a
stepped wedge design to randomize 20 PECARN EMS aﬃliates to implement standardized
dosing in a staggered manner, every four months. Subject accrual will occur over four years.
3.1.1
Age De-Escalation
We will use an age de-escalation strategy for implementation of the standardized dosing
strategy. This is described in more detail in the protocol. For the purpose of the statistical
analyses, unless otherwise speciﬁed in this SAP, age de-escalation will be handled as follows.
Subjects at sites that have transitioned to standardized dosing who are below the current
age de-escalation cutoﬀwill be analyzed in the conventional dosing arm (even though older
children are being treated with standardized dosing). Additional details of the timing of age
de-escalation can be found in Sections 4.2.4 and 4.2.5.
3.2
Method of Treatment Assignment and Randomization
PediDOSE utilizes a stepped wedge design (Figure 1) among the PECARN EMS aﬃliates
to implement standardized dosing in a staggered manner at an EMS agency every 4 months.
Due to the timing of EFIC, the stepped wedge will be implemented in two stages of 10. With
the stepped wedge design, implementation of standardized dosing will be staggered at all 20
sites after a 4-month training period.Figure 1 is presented as an illustrated example and the
true start time of the second cohort will be dependent on training.
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Figure 1: Stepped wedge design
The stepped wedge design randomizes the order in which the sites will transition from
conventional to standardized dosing within the sites of each cohort (the sites that start
earlier and the sites that start later).
Following the approximate timeline in the ﬁgure,
approximately every 4 months per cohort of enrollment, the PECARN DCC will provide
notiﬁcation about randomization to an EMS agency to make the change from conventional
weight–based dosing to standardized age–based dosing. No individual patient randomization
will occur. The allocation will be concealed regarding the timing of when the EMS agency will
switch from conventional to standardized dosing, such that agencies and investigators will
not know when their transition will occur until they receive notiﬁcation about randomization.
In order to allow for the system-wide changes required for implementation, the EMS agency
leadership, other site personnel, and the study PI will be informed up to 2 months prior to
beginning the 4 month training period, after which the new protocol will be implemented.
The ED staﬀmay be aware of the randomization status of the local EMS agency or agencies
participating in the study. Paramedics will be aware of the randomization status of their
own EMS agency when their EMS agency leadership disseminates required online training
and schedules in-person training during the training window.
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3.2.1
Delivery of Randomization
The randomization order of sites will be performed prior to study implementation.
Six
months prior to the site go-live, the site will be notiﬁed of their upcoming transition through
email.
3.2.2
Handling of Incorrect Randomization in Study Analyses and Reports
It is possible that the paramedics use the conventional way of dosing after their site has
transitioned to standardized dosing. Incorrect treatment assignment is discussed more among
various populations for analyses (Section 4.2).
3.3
Treatment Masking (Blinding)
Only unblinded statisticians will be aware of the randomization order from study start.
Paramedics and sites will be aware of what arm they are currently enrolling in. Only a subset
of people at a site will be told of the transition prior to the training transition period.
4
STUDY SUBJECTS AND ANALYSIS POPULA-
TIONS
4.1
Eligibility
This study is enrolling children who have seizures that occur in front of a paramedic in
participating EMS agencies. There are two types of eligibility criteria in this study: protocol
eligibility and analysis eligibility. The study inclusion/exclusion criteria can be found in
the protocol and that describes the populations that can be treated with midazolam. The
analysis eligibility describes the population we perform the analyses on. This is described in
more detail in Section 4.2.3.
4.2
Populations for Analyses
4.2.1
Screening Population
The screening population (SCREEN) includes all patients who are screened for eligibility into
the trial, regardless of treatment with medication. This population represents all patients
who meet inclusion criteria outlined in the study protocol. This population will be used for
reporting of study ﬂow per CONSORT guidelines.
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4.2.2
Eligible/Enrolled Population
The eligible and enrolled population (ENROLLED) includes all SCREEN patients who meet
both inclusion and exclusion criteria and are entered in the database. Note that some enrolled
subjects may withdraw and the outcome data may or may not be available on enrolled
subjects depending on the time of withdrawal. All outcome data available for ENROLLED
subjects will be used in analyses regardless of withdrawal status.
4.2.3
Statistical Analysis Population
The Statistical Analysis population (STAT POPULATION) includes ENROLLED subjects
who meet the statistical analysis criteria who were transported to an aﬃliated hospital. This
excludes the following subjects:
• Presumed or known traumatic head injury within 24 hours of the seizure; OR
• Any prior history of psychogenic, non-epileptic seizures; OR
• Ventilator dependence at the time of the seizure; OR
• Intentional or unintentional ingestion of a medication or substance <24 hours prior to
EMS care, if that medication or substance has the potential to cause seizures or altered
mental status; OR
• Previously enrolled in the study; OR
• Presence of absence seizures during EMS or ED care on the date of enrollment; OR
• Transported to a non-aﬃliated hospital.
4.2.4
Intention-to-Treat Population
The Intention-to-Treat (ITT) population includes all STAT POPULATION subjects, re-
gardless of adherence to the protocol. It also includes subjects who did not receive mida-
zolam. The ITT population will categorize subjects as standardized versus conventional
dosing based on the theoretical dates of their site transition, regardless of when the site
actually transitioned. Events that occurred during the theoretical transition period are not
counted towards either conventional nor standardized dosing. The sites that transition to
standardized dosing prior to the full age de-escalation will be analyzed as follows:
• Subjects that are old enough to be treated with standardized dosing according to the
protocol and DSMB after the transition will be categorized as standardized dosing
• Subjects that are below the current age threshold for receiving standardized dosing
according to the protocol and DSMB will be analyzed as conventional dosing until
1 month after the DSMB gives the approval to de-escalate. Starting 1 month after
the DSMB approval date, the age de-escalated subjects will be categorized as the
standardized arm (even if the site has not oﬃcially changed their protocol).
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4.2.5
As-Treated Population
The As-Treated (AS TREATED) population includes all STAT POPULATION subjects,
regardless of adherence to the protocol. It also includes subjects who did not receive mi-
dazolam. The AS TREATED population will categorize subjects as standardized versus
conventional dosing based on the actual dates of their site transition, regardless of when the
site theoretically should have transitioned. Events that occurred during the actual transi-
tion period are not counted towards either conventional nor standardized dosing. The sites
that transition to standardized dosing prior to the full age de-escalation will be analyzed as
follows:
• Subjects that are old enough to be treated with standardized dosing according to the
protocol and DSMB after the actual transition will be categorized as standardized
dosing
• Subjects that are below the current age threshold for receiving standardized dosing
according to the protocol and DSMB will be analyzed as conventional dosing until the
site actually de-escalates their EMS protocol (requires prior approval at the study level
from DSMB for the de-escalation to be allowed). Starting with the site’s actual EMS
protocol de-escalation date, the age de-escalated subjects will be categorized as the
standardized arm.
Unless otherwise speciﬁed in this SAP, the AS TREATED population is the primary popu-
lation for analysis.
A visual summarizing the ITT and AS-TREATED populations can be seen in Figure 2.
Figure 2: Visual representation of ITT and AS-TREATED analysis populations
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4.2.6
Per-Protocol Population
The Per-Protocol (PP) population includes all STAT POPULATION subjects who were
treated according to how they were to be treated. The categorization of standardized vs
conventional (including age de-escalation) is handled the same as the AS TREATED popu-
lation (Section 4.2.5). All conventional dosed subjects will be included in analysis (including
those who do not receive midazolam). Subjects in the standardized dosing time frame will
be excluded if any dosing method was used besides age based (subjects who do not receive
midazolam will remain in analyses).
4.2.7
Midazolam Population
The Midazolam (MIDAZOLAM) population includes all STAT POPULATION subjects, re-
gardless of adherence to the protocol. It excludes any subject who did not receive midazolam
in the pre-hospital setting. The categorization of standardized vs conventional (including
age de-escalation) is handled the same was as the AS TREATED population (Section 4.2.5).
4.2.8
Safety Population
The Safety (SAFETY) population includes all ENROLLED subjects who receive study drug.
It categorizes the subject exactly how their dose calculation was performed (e.g., age, weight
based).
4.2.9
Visual Representation of Populations
A visual representation of the CONSORT diagram can be found in Figure 3.
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Figure 3: CONSORT diagram summarizing analysis populations
5
GENERAL ISSUES FOR STATISTICAL ANALY-
SES
5.1
Analysis Software
Analysis will be performed using SAS R⃝Software version 9.4 or later whenever possible.
Other software packages, including R and StatXact R⃝, may be used for particular specialized
procedures.
5.2
Methods for Withdrawals, Missing Data, and Outliers
Per the intention-to-treat principle, subjects who withdraw from the study will have all
available data used in the analysis. In the event that a substantial number of subjects are
withdrawn, baseline characteristics and available information on hospital course will be re-
viewed and compared to subjects not withdrawn or lost, to assess empirically if these subjects
diﬀer from those remaining in the study analyses.
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We expect minimal missing data from the hospital course. If a substantial amount of miss-
ingness is to occur, multiple imputation may be performed.
Outliers will be reviewed for validity. Outliers that are valid, for example, high laboratory
values, will be included in all primary reports from this trial.
5.3
Multiple Comparisons and Multiplicity
The secondary outcomes for the PediDOSE will be subject to adjustment of signiﬁcance level
for multiple comparisons. The primary endpoint (seizing upon ED arrival) and the collection
of secondary endpoints (respiratory failure and time to ﬁrst midazolam administration) are
each allocated their own Type I Error rate of 5%. The secondary outcomes will be subject to
Holm’s stepdown procedure. Speciﬁcally, the smallest of the two secondary outcome p-values
will be compared to a signiﬁcance level of 0.05/2 = 0.025. If signiﬁcance is reached from the
ﬁrst comparison, the other secondary outcome p-value will be compared to 0.05.
Tertiary outcomes will not be adjusted for multiple comparisons, as these are more ex-
ploratory in nature. In addition, multiplicity is not adjusted for in subgroup analyses, and
this will be clearly noted in any results published from this trial.
5.4
Planned Subgroups, Interactions, and Covariates
The primary, secondary, and tertiary outcome analyses will be repeated by the following
subgroups to assess possible heterogeneity in treatment eﬀect:
• Method of dose determination (age vs not age)
• Presence vs absence of fever
• New-onset seizure vs previous history of seizures
• Receipt of bystander-administered benzodiazepine prior to EMS arrival
• Route used to administer midazolam
• Sex
• Age
• Presence or absence of hypoglycemia (glucose <60 mg/dL)
• Race/ethnicity
In particular, while controlling for other confounders and the main eﬀects of arm (conven-
tional vs standardized) and the subgroup, we will include an interaction term between arm
and the subgroup of interest within the analysis.
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5.5
Derived and Computed Variables
5.5.1
Data Used in Analyses
There are several variables that are collected from more than one source (e.g., time of ED
arrival). When a variable is collected in more than one spot, unless otherwise speciﬁed in
their respective outcome sections, all outcome data will use the following hierarchy for data
collection data sources as deﬁned in the ﬁgure below.
In the ﬁgure, we summarize several variables that are collected in multiple places in the
database. Within a variable, there are either numbers or ’Yes’ throughout. The numbers
indicate the hierarchy of where information will be pulled from. For example, weight may
be reported on the ED assessment, EMS pre-hospital, and paramedic self report forms. If
weight is not missing on the ED assessment form, that reported weight will be used for an-
alytic purposes. If the ED assessment weight is missing, we will use the weight reported on
the EMS pre-hospital form. If both of those weights are missing, we will use the paramedic
self reported weight. For variables that have ’Yes’, if any source has data that indicates
the event occurred, then the variable will be marked as ’Yes’. For example, if EMS airway
management was reported by the paramedic, on the EMS pre-hospital form, or on the ED
assessment, then the subject will be categorized as needing airway management.
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Figure 4: Data collection sources hierarchy
5.5.2
Ceribell Seizures
Ceribell is a rapid response electroencephalogram (EEG) machine that allows providers
to evaluate if a subject is seizing.
For subjects where the device is placed, one or two
neurologists will review the waveforms and categorize the subject as seizing or not seizing.
If two neurologists review the waveforms and if there is a disagreement in their evaluation,
then a third neurologist will be the tie breaker.
5.5.3
Seizing on ED Arrival
There will be two potential sources for the primary outcome seizing on ED arrival. This
outcome is only assessing the status of whether the subject is seizing upon arrival, not
whether the ﬁrst seizure witnessed by the paramedic is still ongoing. These are described
below.
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Ceribell
Described, in Section 5.5.2, the Ceribell data will be considered for evaluation of
the primary outcome if it was placed on the subject ≤15 minutes after ED arrival.
Healthcare Assessment
The physician and nurse who ﬁrst saw the subject will be asked
to categorize the subject as seizing or not seizing upon hospital arrival. This assessment is
considered for evaluation of the primary outcome if the nurse or physician saw the subject
≤15 minutes after ED arrival. If both the physician and nurse saw the subject in the time
frame, the physician assessment will be used. If neither the nurse or physician saw the pa-
tient ≤15 minutes of ED arrival, then the the paramedic assessment will be used.
The following image (Figure 5) describes the primary outcome derivation. In this image, only
anti-seizure medications given in the ED (excludes EMS) are considered for the medication
column. This also excludes bystander administration of benzodiazepine.
Figure 5: Primary Outcome Hierarchy
The following primary outcome derivation sensitivity analyses may be performed (all in-
tended to be performed on the AS-TREATED population):
• If there is a discrepancy between Ceribell and Healthcare provider (nurse or physician)
seizing status (for situations where both categories are considered for evaluation), then
a blinded adjudication process will be performed to (possibly) re-categorize the subject
as seizing/not seizing.
• The criteria for evaluation of Ceribell time placement will change from 15 minutes to
10 minutes. Other time frames may be used depending on the distribution of Ceribell
time placement.
• The same primary analysis is performed except subjects who are transported to a
non-aﬃliated hospital are also included (currently excluded in the STAT ANALYSIS
population). For those subjects who are transported to a non-aﬃliated hospital, only
the paramedic self report will be available for evaluation.
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5.5.4
Respiratory Failure
The following procedures are considered indication of respiratory failure in this study: BVM,
BiPAP, SGA, CPAP, and ETT.
If the EMS provider, the EMS database, or the hospital medical record indicate the subject
received any of these respiratory failure procedures in the pre-hospital setting or ≤30 min-
utes of ED arrival, then the subject will be categorized as experiencing respiratory failure.
Otherwise the subject will be categorized as not experiencing respiratory failure.
5.5.5
Time to First Midazolam Administration
The time to ﬁrst midazolam administration is calculated as the diﬀerence between time of
ﬁrst dose of midazolam administration and time of paramedic arrival. Subjects who do not
receive midazolam in the pre-hospital setting will have this outcome set to missing.
5.5.6
Time to Seizure Cessation in ED
For subjects who are seizing upon arrival in the ED (according to the primary outcome
derivation described in Section 5.5.3), the time to seizure cessation is calculated as the
diﬀerence between time of seizure cessation and ED arrival. This is derived based on the
ﬁrst observed seizure, not recurrent seizure. The seizure cessation time will be calculated
based on the mechanism used to derive seizure status. For example, if the Ceribell device
was the factor indicating the subject was seizing, the Ceribell time to seizure cessation is
used in the derivation. Subjects who are not seizing upon ED arrival as determined by
Ceribell, doctor, or nurse will be set to missing. Subjects that are still seizing at the time of
last recording or leaving the ED will be considered censored at the last observed time.
5.5.7
Dose/Route Adherence
Weights used in the calculation of dose adherence will be based on the ED weight. Dose/route
adherence will be deﬁned diﬀerently based on what arm they are currently enrolling in ac-
cording to the AS-TREATED population. These are described in more detail below.
Standardized Dosing. For subjects treated under standardized dosing, we will calculate
the the ﬁrst dose that was given to the patient (mg/kg). We will divide the amount in mg
of midazolam by the weight of the child to calculate the dose. The dose will be considered
adherent if the value is ≥0.14 and ≤0.26. The route will be considered adherent if it was
given via IN or IM. The dose/route will be considered adherent if both the dose and the
route are adherent.
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Conventional Dosing. Conventional dosing will be analyzed in a similar framework as the
standardized dosing, except each site’s individual protocols will be considered when calculat-
ing adherence. A dose/route will be considered adherent if the route is through an approved
method and the dose is within 30% of what the site’s EMS protocol allows.
For both the standardized and conventional dosing, only the ﬁrst dose of midazolam is
considered in the adherence calculation.
5.5.8
Life Threatening Hypotension
A subject will be categorized as experiencing life-threatening hypotension if their Systolic
Blood Pressure (SBP) in either the pre-hospital setting or in the hospital setting within 12
hours of ED arrival is below the threshold as deﬁned below and no ﬂuid bolus (normal saline
or lactated ringer) was given.
Children < 12 months:
• SBP < 70
Children ≥1 and <10 years old:
• SBP < 70 + (2 ∗Age)
Children 10 years and older:
• SBP < 90
If a subject received a ﬂuid bolus, the subject will be categorized as experiencing life threat-
ening hypotension if the ﬁrst observed SPB following the end of the bolus is less than the
thresholds deﬁned above. This safety outcome is not dependent on the administration of
midazolam nor the timing of administration if administered.
5.5.9
Life Threatening Cardiac Arrhythmia
A subject will be categorized as experiencing life threatening cardiac arrhythmia if the sub-
ject had Cardiopulmonary resuscitation (CPR), deﬁbrilation, cardioversion with medication,
electrical cardioversion, or pacing in either the pre-hospital setting or within 12 hours of ED
arrival. This safety outcome is not dependent on the administration of midazolam nor the
timing of administration if administered.
5.5.10
Depressed Level of Consciousness
A subject will be considered to have a depressed level of consciousness if the subject observed
a Glasgow Coma Scale (GCS) <8 that persisted for more than 4 hours after ED arrival
(not considered in the pre-hospital setting). This safety outcome is not dependent on the
administration of midazolam nor the timing of administration if administered.
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5.5.11
Method of Dose Determination
Method of dose determination will be categorized as:
• Length
• Age
• Weight
• Paramedic estimate based on overall size
• Other
Only the ﬁrst dose of midazolam will be summarized.
5.5.12
Fever
A subject will be categorized as febrile if the subject has an observed temperature ≥38.5◦C
in either the pre-hospital setting or within 6 hours of ED arrival.
5.5.13
Prior History of Seizure
The subject will be categorized as having a prior history of seizures if they have a prior
history of seizures. Note a prior history of psychogenic, non-epileptic seizures do not count
as having a prior history of seizures.
5.5.14
Receipt of Bystander-Administered Benzodiazepine
A subject will be categorized as receiving bystander administration of benzodiazepine if there
is a known benzodiazepine administration from either the paramedic self report form or the
pre-hospital form. Otherwise the subject will be categorized as not receiving benzodiazepine
(includes conﬁrmed ‘No’ and ’Unknown’).
5.5.15
Route of Midazolam Administration
The ﬁrst dose of midazolam administration will be summarized by the route used. This will
be categorized as one of the following:
• Intramuscular (IM)
• Intranasal (IN)
• Intravenous (IV)
• Intraosseous (IO)
• Rectal (PR)
5.5.16
Time (months) since study start
Time from study start is calculated for each subject as the diﬀerence (months) between the
date the subject was enrolled (as deﬁned as the date the paramedic arrived on scene) and
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the date the ﬁrst site in the study was activated for enrollment.
5.5.17
Age
Subjects will be categorized by the following age groups:
• ≥6 months to <17 months
• ≥17 months to <6 years
• ≥6 years to <12 years
• ≥12 years to <14 years
5.5.18
Hypoglycemia
A subject will be categorized as hypoglycemic if the subject’s ﬁrst observed glucose is <60
mg/dL.
5.6
Independent Review
All statistical analyses for primary reporting of trial results will be independently veriﬁed
through dual programming. Two statisticians will each program all datasets and analyses
for the DSMB reports and the primary manuscript(s) and the results will be compared. This
process will begin at the analysis design stage and will continue through writing of abstracts
and manuscripts.
6
INTERIM ANALYSES
6.1
Frequency of and Timepoints for Interim Analysis
The DCC will perform limited interim safety analysis at the end of each year of patient
enrollment in order to prepare a report for the DSMB to determine whether or not the lower
age limit for standardized dosing can be de-escalated. An interim safety and eﬀectiveness
analysis will be provided to the DSMB after 3 years.
6.2
Stopping Rules for Interim Eﬃcacy Analysis
A symmetric, two-sided O’Brien-Fleming type boundary with overall alpha level set to 0.05
will be used as a guideline for stopping the study due to a diﬀerence between treatment
arms. Stopping boundaries will be generated using symmetric monitoring boundaries, corre-
sponding to alpha spending of 0.025 to detect a beneﬁt and 0.025 to detect a harmful eﬀect
of intervention vs standard of care. Lan-DeMets spending functions [1] corresponding to
O’Brien-Fleming type boundaries [4] will be used.
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The information fraction after 3 years is expected to be 0.716. Using the ldBounds package
in R and assuming a look at 0.716 and 1.000 (ﬁnal look) information fractions, the thresholds
for statistical signiﬁcance at the two looks are:
• 3 Years (0.716): -2.40547 to 2.40547
• 4 Years (1.000): -2.00350 to 2.00350
This process will be performed using the true ICC at the interim look. Full details of how
the interim information fraction is calculated can be found in Appendix A.
6.3
Blinding in the Interim Analysis
All parties involved will be aware when a site has transitioned to standardized dosing. Only
the DSMB and DCC statisticians will be aware of aggregate summaries in the DSMB report
and the interim analysis results. Due to the nature of the stepped wedge design, it is not
possible to blind DSMB members of treatment assignment in aggregate summaries.
7
PLANNED ANALYSES
7.1
Description of Subject Characteristics
Publication of the primary results will include reporting of key baseline characteristics overall,
and by assigned treatment arm. These will include, but are not limited to
• Sex
• Race
• Ethnicity
• Age
7.2
Primary Outcome Analysis
The primary outcome will be analyzed using a mixed logistic regression with a random eﬀect
for site. The main predictor of interest is arm (conventional weight-based vs standardized
age-based dosing). We will control for the logistic regression with the following covariates:
• Fever
• Previous history of seizures
• Receipt of bystander-administered benzodiazepine prior to EMS arrival
• Time since study start
• Subject sex
• Subject age
• Presence of hypoglycemia
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Depending on convergence and potentially small cell counts, non-signiﬁcant covariates may
be removed. In addition other covariates may be removed if there is evidence of collinearity.
7.2.1
Additional Analyses of Primary Outcome
In addition to the sensitivity deﬁnitions of the primary outcome described in Section 5.5.3,
the primary outcome analysis will be repeated in the ITT, PP, and MIDAZOLAM popula-
tions. For the MIDAZOLAM sensitivity analysis, we will also control for route of adminis-
tration and, if no collinearity exists, method for dose determination.
To analyze if there is a waning eﬀect of standardized dosing paramedic training, an additional
sensitivity will be performed to assess time since transition period initiation. Subjects will
be categorized into one of the following categories (based on each site’s individual transition
period):
• Conventional weight based dosing
• Standardized dosing - enrolled ≤6 months since transition period
• Standardized dosing - enrolled 7 to ≤12 months since transition period
• Standardized dosing - enrolled 13 ≤18 months since transition period
• Standardized dosing - enrolled more than 18 months since transition period
We will repeat the primary outcome and control for the same variables except time since
study start. The parameter estimates for the standardized dosing will allow us to evaluate
if the overall eﬀect of training diminishes over time.
7.3
Secondary Outcome(s) Analyses
7.3.1
Respiratory Failure
Respiratory failure will be analyzed in an identical way as the primary outcome and will
control for the same covariates. The analysis may be repeated for the ITT, PP, and MIDA-
ZOLAM populations, but the AS-TREATED is the primary population of interest. Similar
to the primary outcome, the MIDAZOLAM sensitivity analysis may control for route of
administration and method for dose determination.
7.3.2
Time to First Midazolam Administration
Time to ﬁrst midazolam administration will be analyzed using a linear regression with a
random eﬀect for site. The same covariates controlled for in the primary outcome will be
controlled for in this secondary outcome in addition to route of administration (and possibly
method for dose determination). Due to the nature of this analysis, it will be performed in
the MIDAZOLAM population. The analysis may be repeated for the ITT and PP, removing
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subjects in each population who do not receive midazolam, but the MIDAZOLAM is the
primary population of interest.
7.4
Tertiary Outcome(s) Analyses
7.4.1
Time to Seizure Cessation in ED
Time to seizure cessation in ED will be analyzed using a Cox proportional hazards model.
This analysis will adjust for all variables controlled for in the primary outcome regression.
Subjects that never stop seizing will be censored at the time of Ceribell removal or ED
disposition time. The analysis will be performed only on subjects seizing upon ED arrival
that have a cessation or censor time.
7.4.2
Dose/Route Adherence
Dose/route adherence will be analyzed in a similar framework as the outcome Time to First
Midazolam Administration (Section 7.3.2) except a logistic regression with a random eﬀect
for site will be used. This will be performed on the MIDAZOLAM population.
7.5
Technical Approaches for Subgroup Analyses
Subgroup analyses will be performed to assess the primary, secondary, and exploratory out-
comes with respect to each of the variables controlled for in the model used to analyze the
primary outcome (listed above). The regressions mentioned above will include the main eﬀect
for the subgroup and an interaction term between the subgroup variable and arm. For sub-
groups that are related to the administration of midazolam, the MIDAZOLAM population
will be used for analyses.
7.6
Safety Analyses
7.6.1
Formal Safety Outcome(s)
Formal safety outcome analyses for Life Threatening Hypotension, Life Threatening Cardiac
Arrhythmia, and Depressed Level of Conciousness are all analyzed in a similar framework
as described below.
The primary analyses of each safety outcome will be compared between arms using a Mantel-
Haenszel test, stratiﬁed by site. Fisher’s Exact test stratiﬁed by site will be used in cases of
small counts.
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7.6.2
Adverse Events
Adverse events (AEs) will be recorded as described in the protocol. Adverse events will be
coded using the latest version of Medical Dictionary for Regulatory Activities (MedDRA).
All Adverse Events
Summaries of incidence rates (frequencies and percentages), inten-
sity, and relationship to study of individual AEs by System Organ Class and Preferred Term
(MedDRA) will be prepared. Basic summaries by assigned groups will be prepared. The
DSMB may request to see more detailed tables. The occurrence of any adverse event will
be considered as a dichotomous outcome and will be compared between groups using a
Mantel-Haenszel test, stratiﬁed by site.
Serious Adverse Events/Deaths
SAEs/Deaths will be reported separately in a similar
fashion to the more general AE reports. In addition, narratives will be available for each
event.
8
SAMPLE SIZE DETERMINATION
The frequency of seizing on ED arrival was estimated through simulation based on hypoth-
esized frequencies for both conventional dosing and standardized dosing and based on prior
data as described in the protocol. The simulations used for calculating the sample size using
the stepped wedge (SW) design accounted for the site-to-site variability in enrollment. The
simulations assume a constant start time for all sites, so actual power will depend on when
the second cohort of sites actually starts enrollment. Only randomization sequences that
have an expected enrollment size for the conventional and standardized dosing arms within
5% of each other at the end of the trial will be considered. We expect to see 1,210 active
pediatric seizure cases per year. Seizure cases that are observed during the SW transition
periods are not counted towards either arm. Accounting for an 8% intra-cluster correlation,
up to 10% lack of identiﬁcation of eligible patients and exclusion of seizures during transition
periods, we expect to see at least 820 seizure cases per year eligible for analyses. Based on
this and the design matrix in 1, we approximate 87% power to detect a diﬀerence from a
seizing on ED arrival rate of 39% in the conventional dosing arm and 29% in the standardized
dosing arm in the 6 month – 13 year old patients.
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9
References
References
[1] David L. Demets and K. K. Gordon Lan. Interim analysis: The alpha spending function
approach. 13:1341–1352, 1994.
[2] Karla Hemming, Richard Lilford, and Alan J. Girling.
Stepped-wedge cluster ran-
domised controlled trials: a generic framework including parallel and multiple-level de-
signs. 34:181–196, 2015.
[3] Michael A. Hussey and James P. Hughes. Design and analysis of stepped wedge cluster
randomized trials. 28:182–191, 2007.
[4] Peter C. O’Brien and Thomas R. Fleming. A multiple testing procedure for clinical trials.
35:549, 1979.
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A
INTERIM LOOK INFORMATION SPENDING
In this section, we describe the calculations behind the determination of alpha spending for
the statistical design matrix. Monitoring boundaries will be set according to the propor-
tion of total statistical information (information fraction) available in the interim analysis
dataset. For many trial designs, the information fraction would simply be the proportion of
total anticipated subjects that have been enrolled prior to the interim analysis. However, the
more complex design and analysis of this trial requires a diﬀerent formula for the information
fraction. The information fraction is deﬁned as the ratio of the estimated variance of the
treatment eﬀect estimator at the end of the trial compared to the estimated variance at the
current stage of the trial. For a complete design, Hussey and Hughes (2007) [3] provide a
formula for the variance (Equation 8 in their paper).
For the stepped wedge design, let the stepped wedge design described in Figure 1 be repre-
sented by Figure 6 below.
Figure 6: Statistical representation of stepped wedge design
Let Xij = 0 if an individual cluster (site) i is receiving conventional dosing at time j and
Xij = 1 if an individual cluster i is receiving standardized dosing at time j based on the
theoretical design (i.e., Xij is the cell in the table for row i column j).
Hemming, Lilford, and Girling (2014) [2] extend the Hussey and Hughes logic to incomplete
designs such as ours (in Section 4.3 of their paper) by demonstrating how to handle transition
periods or periods where a site might not be actively enrolling (represented by the decimal
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places in Figure 6). In particular, the transition periods or periods of non enrollment do not
contribute to the information available. We recognize all sites not transition precisely at the
start and end of their randomized time intervals, but the design matrix will still be used
for the derivation of information fraction unless the trial has a major deviation from that
plan. According to Hemming, Lilford, and Girling, we can transform the statistical matrix
in Figure 6 to be represented by one row per site per period where enrollment is occurring
(excludes delayed start and transition periods in our design matrix). A column for time
period and columns for site indicators are also included. A basic example of this is shown
below in Figure 7 from our statistical design matrix for the ﬁrst 6 data collection periods
in Sites 1 and 11. In this matrix which we deﬁne as D, the column X represents whether
the site period was on conventional dosing (0) or standardized dosing (1). The column J
represents the time period from the stepped wedge design (ranges from 1-48). The remaining
columns are indicators for the site each row is represented by.
Figure 7: Transformed matrix of stepped wedge design
To calculate the variance of the treatment eﬀect (column X) for this D matrix, assume the
following:
• D is a pxq matrix
• θ is a q vector corresponding to the estimates of each column in D
• τ 2 is the between-cluster variance
• σ2 is the natural variability of the estimates
The qxq covariance matrix of D can be denoted by:
V ar(ˆθ) = [(X′X)−1X′]V (y)[(X′X)−1X′]′
where
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V (y) = (τ 2 + σ2Imi)|I
i=1
V (y) is a block diagonal matrix where each site has a block size equivalent to the number of
periods they are enrolling in (deﬁned as mi in the equation above which has a maximum of
44 for 44 months of active enrollment). Within a site, the variance of the eﬀect for a single
period is σ2 and between periods the covariance is σ2 + τ 2. Between sites, the covariance is
0. Visually, V (y) can be shown as in Figure 8. In this ﬁgure we illustrate two site’s blocks
with a green and blue rectangle.
Figure 8: Covariance matrix of transformed design matrix
At a given period, the variance of the treatment eﬀect (column X in matrix D) is captured
by V ar(ˆθ)[1, 1]. To calculate the information fraction, we will compare the variance estimate
of the treatment eﬀect using the full design matrix and the partial design matrix available
after 3 years. This can be annotated as:
V ar(ˆθ|Full Design Matrix)
V ar(ˆθ|Portion of Design Matrix Observed at 37 Months)
An estimate of the intra-cluster correlation (ICC) is required to calculate the information
fraction. For the purposes of demonstrating the calculation of information fraction, we will
assume an intracluster correlation of 0.08, but the true estimated intracluster correlation
from modeling once the analysis is performed at 3-years will be used for the interim. The
information fraction described in Section 6.2 is calculated from this logic.
Assuming an ICC of 0.08 and the design matrix above, after 36 months of enrollment, the
information fraction is 0.716. Using the ldBounds package in R and assuming a look at 0.716
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and 1.000 (ﬁnal look) information fractions, the thresholds for statistical signiﬁcance at the
two looks are:
• 3 Years (0.716): -2.40547 to 2.40547
• 4 Years (1.000): -2.00350 to 2.00350
This process will be performed using the true ICC at the interim look.
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