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Confidential
03-Jun-2014
Version 1.0
Epidemiology and Inpatient Management of Patients
Hospitalized for Acute Asthma: 37th Multicenter Airway
Research Collaboration (MARC-37) Study
Author(s):
__________________, MD (Site Investigator)
Carlos A. Camargo, MD, DrPH (Principal Investigator;
Emergency Medicine Network Coordinating Center,
Massachusetts General Hospital)
Version number:
1.0
Release date:
03-Jun-2014
Number of pages:
23 pages + data collection instruments
Grant support
This study is supported by a grant from Novartis to the
Massachusetts General Hospital.
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Non-interventional study protocol
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Product number/name/Study number
Table of contents
Table of contents ................................................................................................................. 2
List of abbreviations ............................................................................................................ 4
Protocol synopsis ................................................................................................................ 5
1 Background ......................................................................................................................... 8
2 Purpose and rationale .......................................................................................................... 8
3 Objectives ............................................................................................................................ 8
4 Study design ........................................................................................................................ 9
5 Population and setting ......................................................................................................... 9
5.1
Inclusion criteria ...................................................................................................... 9
5.2
Exclusion criteria ................................................................................................... 10
5.3
Data sources .......................................................................................................... 10
5.4
Study completion ................................................................................................... 10
5.5
Premature study discontinuation ........................................................................... 10
6 Data collection/measurement ............................................................................................ 11
6.1
Patient demographics/characteristics .................................................................... 11
6.2
Site Survey ............................................................................................................ 12
6.3
Medications of interest .......................................................................................... 12
6.4
Outcomesof interest ............................................................................................... 13
6.5
Safety related measurements ................................................................................. 13
7 Safety monitoring .............................................................................................................. 13
8 Data analysis ..................................................................................................................... 14
8.1
Patient demographics/other baseline characteristics ............................................. 14
8.2
Drug exposure ....................................................................................................... 14
8.3
Analysis of the main objectives............................................................................. 14
8.3.1
Primary Variables ................................................................................. 14
8.3.2
Handling of missing values/censoring/discontinuations....................... 15
8.3.3
Other ..................................................................................................... 15
8.4
Sample size/power calculation .............................................................................. 15
9 Data monitoring and quality control ................................................................................. 15
9.1
Site monitoring ...................................................................................................... 15
9.2
Data recording and document retention ................................................................ 16
9.3
Data quality assurance ........................................................................................... 16
10 Limitations ........................................................................................................................ 16
11 Ethical considerations ....................................................................................................... 16
11.1 Regulatory and ethical compliance ....................................................................... 17
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11.2 Informed consent procedures ................................................................................ 17
11.3 Responsibilities of the site investigator and IRB .................................................. 17
11.4 Early termination of study ..................................................................................... 18
11.5 Publication of study protocol and results .............................................................. 18
11.6 Protocol adherence and amendments .................................................................... 18
12 References ......................................................................................................................... 19
13 Appendices ........................................................................................................................ 22
13.1 Appendix 1 Description of quality measures for inpatient acute asthma care ...... 22
13.2 Appendix 2 Data collection instruments ................................................................ 23
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List of abbreviations
CRF
Case Report/Record Form
eCRF
electronic Case Report/Record Form
ED
Emergency Department
EMNet
Emergency Medicine Network
ENCePP
European Network of Centres for Pharmacoepidemiology and
Pharmacovigilance
EPR-3
Expert Panel Report 3
GPP
Good Pharmacoepidemiology Practices
ICD-9-CM
International Classification of Diseases, Ninth Revision, Clinical
Modification
IRB
Institutional Review Board
ISPE
International Society for Pharmacoepidemiology
MARC
Multicenter Airway Research Collaboration
NAEPP
National Asthma Education and Prevention Program
NIH
National Institutes of Health
NIS
Non-interventional Study
PEF
Peak expiratory flow
PHI
Protected health information
PI
Principal Investigator
REDCap
Research Electronic Data Capture
SOP
Standard Operating Procedure
STROBE
Strengthening the Reporting of Observational Studies in Epidemiology
UHC
University HealthSystem Consortium
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Protocol synopsis
Title of study: Epidemiology and Inpatient Management of Patients Hospitalized for Acute
Asthma: 37th Multicenter Airway Research Collaboration (MARC-37) Study
Version and Date: Version 1.0. 31-May-2014
Name and affiliation of site investigator:_____________, MD; _______________Hospital.
Background: Asthma hospitalizations represent a serious adverse outcome. In addition, the
public health burden of asthma hospitalizations remains significant: 385,000 asthma-related
hospitalizations in 2011, with an estimated direct cost of $ 2.3 billion annually. In a prior 30center inpatient study (the University HealthSystem Consortium [UHC] Asthma Clinical
Benchmarking Project in 1999-2000), we demonstrated sex and racial/ethnic differences in
asthma presentations and quality of inpatient care. However, current information on the
epidemiology of patients hospitalized for acute asthma and the quality of inpatient asthma
care is scarce. Furthermore, although the 2007 Expert Panel Report 3 (EPR-3) guidelines
recommended referral to asthma specialist for patients with asthma hospitalization, there has
been limited research on post-hospitalization asthma care. The current study will address
these knowledge gaps and facilitate studies to implement preventive measures for this highrisk and costly population.
Purpose and rationale: To assist ongoing efforts to improve inpatient and posthospitalization management of asthma and to reduce the burden of healthcare utilization and
associated health care expenditures, the study will characterize today’s hospitalized asthma
patients, to determine the concordance of their inpatient care with national asthma guidelines,
and to characterize the post-hospitalization asthma care. The results will facilitate studies to
implement preventive measures for this high-risk and costly population.
Objectives: The study objective includes:
(1)
To describe hospitalized patients with acute asthma.
(2)
To quantify the proportion and characteristics of patients with at least one
asthma hospitalization in the 12 months before their index hospitalization.
(3)
To evaluate the concordance of current inpatient management of acute asthma
with the 2007 EPR-3 guidelines.
(4)
To describe post-hospitalization asthma care, including referral to an asthma
specialist, allergy testing, and any adjustments to patients’ long-term controller
medications.
Study design: We will conduct a multi-center chart review study examining a total of 1000
patients hospitalized with acute asthma to assess their current characteristics and inpatient
management in 25 hospitals across the USA. MARC-37 study will be coordinated by EMNet
(based at Massachusetts General Hospital), a research collaboration with >225 participating
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hospitals. EMNet will recruit the 25 hospitals by inviting all 30 sites that conducted the UHC
study in 1999-2000.
Using a standardized protocol, investigators at each participating hospital will perform data
abstraction from 40 randomly selected charts to collect information about patients
hospitalized for acute asthma.
Population: MARC-37 sites will use hospital administrative records and the International
Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 493.xx,
to identify all charts with a principal hospital discharge diagnosis of asthma during a 12month period, between January 1, 2012 to December 31, 2013 (i.e., 24-month window). The
hospital visit chosen for chart review will be selected at random from all asthma-related
hospital visits over the 12-month period; the randomly-selected visit will not necessarily be
the first visit by the patient during the 12-month period. Each site will randomly sample at
least 40 visits for chart review (40 visits/site x 25 sites = 1000 visits).
Inclusion/Exclusion criteria:
1) Inclusion criteria are: 1) patients aged 2 to 54 years 2) a history of asthma before
the index hospitalization
2) Exclusion criteria are: 1) hospitalizations made by patients with a history of cystic
fibrosis or chronic obstructive pulmonary disease, 2) transfer hospitalizations, and
3) repeat hospitalizations by the same subject (i.e., each hospitalization in the
study database will represent a unique patient).
Data sources: MARC-37 investigators will examine a total of 1000 patients. At each of the
25 sites, chart abstractors will review 40 charts that were randomly selected by the EMNet
Coordinating Center at Massachusetts General Hospital.
Exposure to medication(s) of interest and comparator therapy: Medications of interest
include:
1)
Regular asthma medications (e.g., inhaled beta-agonists, inhaled
corticosteroids, leukotriene modifiers, omalizumab, systemic corticosteroids) before
the index hospitalization
2)
Preadmission treatments (e.g., inhaled beta-agonists, inhaled anticholinergics,
systemic corticosteroids, intravenous magnesium)
3)
Discharge medications (e.g., systemic corticosteroids, inhaled corticosteroids,
leukotriene modifiers)
4)
Post-hospitalization long-term controller treatment (e.g., inhaled
corticosteroids, long-acting β2 agonists, and omalizumab)
Outcomes of interest:
(1)
Outcomes for Aim 1 include patient demographics (e.g., socioeconomic
factors, smoking), past asthma history (e.g., number of asthma emergency department
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visits in the past year), chronic asthma medications, and laboratory testing (e.g., total
and specific IgE levels).
(2)
year.
The outcome for Aim 2 is the frequency of asthma hospitalizations in the past
(3)
Outcomes for Aim 3 are guideline-concordance scores (calculated from
inpatient asthma treatments and discharge factors).
(4)
Outcomes for Aim 4 include referral to an asthma specialist, allergy testing,
and any adjustments to long-term controller medications.
Safety related measurements: Not applicable
Data analysis: All analyses will be performed by the EMNet Coordinating Center at
Massachusetts General Hospital (Boston, MA).
Summary statistics at both the patient- and site-levels will be presented as proportions (with
95% confidence intervals), means (with standard deviations), or medians (with interquartile
ranges) (Aims 1 and 4). Then, patients will be classified into two inpatient utilization groups
based on their number of asthma hospitalizations in the 12 months before their index
hospitalization (Aim 2). Patients will be categorized as “no asthma hospitalization in past
year” and one or more hospitalizations in the past 12 months. We will describe the summary
statistics of the outcomes of interest in each stratum. The association between the number of
hospitalizations and the outcomes of interest will be examined. Finally, we will calculate the
10 inpatient evidence-based process measures (Appendix 1) at the patient-level (Aim 3).
These scores then will be averaged across patients at the hospital-level to obtain inpatient
composite scores. Associations between hospital characteristics and composite concordance
scores will be assessed by using multivariable linear regression, adjusting for aggregate
patient mix at the hospital level.
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Background
Asthma hospitalizations represent a serious adverse outcome that is theoretically preventable
with optimal management of asthma. Although several cost-effective preventive measures are
available, 1 the public health burden of asthma hospitalizations remains significant: 385,000
asthma-related hospitalizations in 2011, with an estimated direct cost of $ 2.3 billion annually
(and an estimated charge of $ 8 billion).2 In this context, the US government identified the
reduction of hospitalizations for acute asthma as a national objective in Healthy People 2020
through better prevention, treatment, and education efforts. In a prior 30-center inpatient
study (the University HealthSystem Consortium [UHC] Asthma Clinical Benchmarking
Project in 1999-2000),3 we demonstrated sex and racial/ethnic differences in asthma
presentations and quality of inpatient care.4-6 However, current information on the
epidemiology of patients hospitalized for acute asthma and the quality of inpatient asthma
care is scarce. Furthermore, although the 2007 Expert Panel Report 3 (EPR-3) guidelines
recommended referral to an asthma specialist for patients with asthma hospitalization, there
has been limited research on post-hospitalization asthma care.
2
Purpose and rationale
To assist ongoing efforts to improve inpatient and post-hospitalization management of asthma
and to reduce the burden of healthcare utilization and associated health care expenditures, the
study will characterize today’s hospitalized asthma patients, to determine the concordance of
their inpatient care with national asthma guidelines, and to characterize the posthospitalization asthma care. The results will facilitate studies to implement preventive
measures for this high-risk and costly population.
3
Objectives
The study objectives include:
Aim 1: To describe hospitalized patients with acute asthma.
Aim 2: To quantify the proportion and characteristics of patients with at least one
asthma hospitalization in the 12 months before their index hospitalization.
Aim 3: To evaluate the concordance of current inpatient management of acute asthma
with the 2007 EPR-3 guidelines.
Aim 4: To describe post-hospitalization asthma care, including referral to an asthma
specialist, allergy testing, and any adjustments to patients’ long-term controller
medications.
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Study design
We will conduct a multi-center chart review study of 1000 patients hospitalized with acute
asthma in 25 hospitals across the USA. MARC-37 study will be coordinated by EMNet (based
at Massachusetts General Hospital), a research collaboration with >225 participating hospitals.
It will build on the success of the UHC study in 1999-2000,3 by updating observational data
from 25 general and children’s hospitals in that prior study. Using a standardized protocol,
investigators at each participating hospital will perform data abstraction from 40 randomly
selected charts to collect information about patients hospitalized for acute asthma.
Before data collection, each MARC-37 site will obtain Institutional Review Board (IRB)
approval of the protocol, with waiver of informed consent for the chart review study and
informed consent implied through voluntary completion of the online site survey. Copies of
all IRB approvals will be retained by EMNet Coordinating Center.
5
Population and setting
We will identify hospitalizations during a 24-month period to facilitate implementation of the
study across the 25 sites. Although we will encourage all sites to start with calendar year 2013
(i.e., January 2013 to December 2013), some sites will not be able to run a calendar year 2013
search until later in 2014. Others will prefer to work within their fiscal year (e.g., July 2012June 2013; Oct 2012-Sep 2013) because data are more readily available for that time period.
Each site will identify hospitalizations with a principal hospital discharge diagnosis of asthma
during a 12-month period. The EMNet Coordinating Center will randomly select at least 40
hospitalizations for chart review. The exclusion criteria will require that some sites sample
>40 to yield 40 eligible hospitalizations. For example, random sampling may yield two
hospitalizations by the same person; the hospitalization that was sampled first will be retained
for chart review, unless it is otherwise ineligible (e.g., transfer). We will avoid systematic
retention of the earlier hospitalization during the 12-month period (e.g., choosing January
hospitalization before May hospitalization) to avoid over-representation of hospitalizations
that occurred earlier in the 12-month period, which often will be based on calendar year. The
review of 40 hospitalizations per site, at 25 sites, will yield a database with 1000
hospitalizations. Each hospitalization will represent a unique patient.
5.1
Inclusion criteria
Inclusion criteria are:
1) Patients aged 2 to 54 years with a history of asthma before the index
hospitalization, and
2) Patients with a principal hospital discharge diagnosis of asthma during a 12-month
period between January 1, 2012 to December 31, 2013 (i.e., 24-month window)
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Exclusion criteria
Exclusion criteria are:
1) Hospitalizations made by patients with a history of cystic fibrosis or chronic
obstructive pulmonary disease
2) Transfer hospitalizations, and
3) Repeat hospitalizations by the same subject
5.3
Data sources
MARC-37 investigators will examine a total of 1000 hospitalized patients. At each of the 25
sites, chart abstractors will review 40 charts randomly selected by the EMNet Coordinating
Center using a random numbers table. All sites will have >40 acute asthma charts in the
preceding 12-month period. Chart abstractors will have some medical training, with the vast
majority being physicians, nurses, or respiratory therapists. Abstractors will be trained by the
EMNet Coordinating Center, and then the abstractors will complete two practice charts,
which will be assessed versus a ‘‘criterion standard.’’ If an abstractor’s accuracy is less than
80% per chart, the individual will be retrained. Online tools (e.g. an extensive Manual of
Procedures) will be available for abstractors. Since all forms already have been adapted from
forms used in prior successful studies,3-21 we are confident that the forms will function well
across the 25 sites in the MARC-37 study.
Data will be entered directly into an online database, using the National Institutes of Health
(NIH)-sponsored Research Electronic Data Capture (REDCap).22 REDCap is a secure, webbased, electronic database hosted at Massachusetts General Hospital, and is being used in
several ongoing EMNet studies. All data entered into REDCap by site investigators will
undergo further review by the MARC-37 Project Coordinator and trigger specific data
queries, as needed. Access to the REDCap database will be limited to study personnel only
and require an individual assigned username and password. The REDCap database will be
exported into Microsoft Excel and then imported into Stata for statistical analysis. All files
will be kept on secure, password-protected servers at Massachusetts General Hospital.
5.4
Study completion
Each site will complete the study when they complete their site survey, submit data from 40
randomly-selected charts, and have answered any queries about their submitted chart review
data.
5.5
Premature study discontinuation
Not applicable.
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Data collection/measurement
This is a non-interventional study and does not impose a therapy protocol,
diagnostic/therapeutic procedure, or a visit schedule. Patients will be treated according to the
local prescribing information, and routine medical practice in terms of visit frequency and
types of assessments performed and only these data will be collected as part of the study.
6.1
Patient demographics/characteristics
Data abstracted from charts will include:
 Baseline patient characteristics (e.g., age, sex, race/ethnicity, home ZIP code [to
assign median household income], primary care physician status, primary insurance,
pregnancy status, smoking history, obesity, other comorbid conditions)
 Past asthma history (e.g., age of diagnosis, history of hospitalization and/or intubation
secondary to asthma, frequency of asthma-related hospitalizations and ED visits
during the 12 months before the index hospitalization, outpatient management by an
asthma specialist)
 Laboratory testing at each study site over the 12 months before the index
hospitalization (e.g., total IgE, specific IgE, skin-prick testing)
 Regular asthma medications (e.g., inhaled beta-agonists, inhaled corticosteroids,
leukotriene modifiers, omalizumab, systemic corticosteroids) and medication
adherence before the index hospitalization
 Location of preadmission assessment (e.g., ED, clinic/office)
 Preadmission presentation (e.g., season, time of arrival, vital signs, peak expiratory
flow)
 Preadmission treatments (e.g., inhaled beta-agonists, inhaled anticholinergics,
systemic corticosteroids, intravenous magnesium) and their timing relative to the
patient’s ED/clinic arrival time
 Initial hospital admission location (e.g., observation unit, hospital ward, intensive care
unit)
 Inpatient management (e.g., laboratory testing [e.g., total IgE] and treatment)
 Disposition (home, died in hospital, other)
 Length of stay (inpatient, intensive care unit)
 Discharge medications (e.g., systemic corticosteroids, inhaled corticosteroids,
leukotriene modifiers)
 Discharge plan (e.g., asthma action plan at discharge, follow-up appointment.
 Post-hospitalization asthma care (e.g., referral to an asthma specialist, allergy testing,
and any adjustments to long-term controller treatment [e.g., inhaled corticosteroids,
long-acting β2 agonists, and omalizumab]).
To avoid privacy concerns, sites will not send any protected health information (PHI) to the
EMNet Coordinating Center. Specifically, patient date of birth, date of hospitalization, date of
hospital discharge, and ZIP code will be collected on the Chart Review Log and converted, as
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necessary, to non-PHI data. For example, date of birth will yield age in years. Likewise, ZIP
code will be used to look up specific information of interest (e.g., median household income).
Peak expiratory flow (PEF) is recorded in liters per minute and expressed as the absolute
value. Severity of acute asthma will be classified according to the initial PEF as follows: mild,
300 L/min or greater for women and 400 L/min or greater for men; moderate, 200 to 299
L/min for women and 250 to 399 L/min for men; severe, 120 to 199 L/min for women and
150 to 249 L/min for men; and very severe, less than 120 L/min for women and less than 150
L/min for men. The absolute PEF values represent approximately 70%, 40%, and 25% of
predicted value, respectively, for a typical adult woman and man. 23
6.2
Site Survey
A preliminary online survey (Site Survey) of each MARC-37 site investigator to collect data
on hospital characteristics, such as:
 Annual number of ED visits for acute asthma, by age group
 Annual number of hospitalizations for acute asthma, by age group
 US region
 Urban/rural designation
 Teaching hospital status
 Affiliation with an internal medicine residency program
 Affiliation with an allergy/immunology or pulmonary medicine fellowship program
Geographic regions (Northeast, South, Midwest, and West) will be defined according to
Census Bureau boundaries. 24 Rural and urban distinctions will be made according to the
Office of Management and Budget’s designation of metropolitan statistical area. 25
6.3
Medications of interest
Medications of interest include:
1) Regular asthma medications before the index hospitalization
 Inhaled beta-agonists
 Inhaled corticosteroids
 Leukotriene modifiers
 Omalizumab
 Systemic corticosteroids
2) Preadmission treatments
 Inhaled beta-agonists
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 Inhaled anticholinergics
 Systemic corticosteroids
 Intravenous magnesium
3) Discharge medications
 Systemic corticosteroids
 Inhaled corticosteroids
 Leukotriene modifiers
4) Post-hospitalization long-term controller treatments
 Inhaled corticosteroids
 Long-acting β2 agonists
 Omalizumab
6.4
Outcomes of interest
1) Outcomes for Aim 1 include patient demographics (e.g., socioeconomic factors,
smoking), past asthma history (e.g., number of asthma emergency department visits in
the past year), chronic asthma medications, and laboratory testing (e.g., total and
specific IgE levels).
2) The outcome for Aim 2 is the frequency of asthma hospitalizations in the past year.
3) Outcomes for Aim 3 are guideline-concordance scores (calculated from inpatient
asthma treatments and discharge factors).
4) Outcomes for Aim 4 include referral to an asthma specialist, allergy testing, and any
adjustments to long-term controller medications.
6.5
Safety related measurements
Not applicable.
7
Safety monitoring
As this is a study based on secondary data sources, safety monitoring and safety reporting on
an individual case level is not applicable. In studies based on secondary data sources with a
safety relevant result, only aggregated safety results, i.e. the overall association between an
exposure and an outcome, should be reported and be included in the periodic aggregated
regulatory reports submitted to Health Authorities.
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Data analysis
All analyses will be performed by the EMNet Coordinating Center at Massachusetts General
Hospital (Boston, MA).
8.1
Patient demographics/other baseline characteristics
Summary statistics at both the patient- and site-levels will be presented as proportions (with
95% confidence intervals), means (with standard deviations), or medians (with interquartile
ranges).
8.2
Drug exposure
Not applicable.
8.3
Analysis of the main objectives
8.3.1
Primary Variables
Summary statistics at both the patient- and site-levels will be presented as proportions (with
95% confidence intervals), means (with standard deviations), or medians (with interquartile
ranges) after assessing the data for normality (Aims 1 and 4).
For Aim 2, the patients will be classified into 2 inpatient utilization groups based on their
number of asthma hospitalizations in the 12 months before their index hospitalization.
Patients will be categorized as “no asthma hospitalization in past year” and one or more
hospitalizations in the past 12 months. First, unadjusted associations between patient
characteristics (e.g., demographics, past asthma history, chronic asthma medications) and
hospitalization status will be tested with using Student t-test, chi-square, Fisher’s exact, or
Wilcoxon rank sum test, as appropriate. Second, multivariable multinomial logistic regression
models will be fit to examine independent associations between patient characteristics and
hospitalization status, with no prior hospitalization group as the reference.
For Aim 3, we will compute the 10 inpatient evidence-based process measures at the patientlevel. On the basis of common recommendations in the 2007 EPR-3 asthma guidelines, 23 and
in the consensus view of the EMNet Steering Committee, we will examine 10 process
measures among patients eligible to receive these treatments. These process measures include
5 level A and 5 level B evidence-based inpatient treatments (total 10) according to the EPR-3
guidelines (see Appendix 1). Level A evidence requires substantial numbers of randomized
controlled trials involving substantial numbers of participants, while level B requires fewer
randomized controlled trials involving fewer numbers of participants. These scores then will
be averaged across patients at the hospital-level to obtain inpatient composite scores.
Associations between hospital characteristics and composite concordance scores will be
assessed by using multivariable linear regression, adjusting for aggregate patient mix (age,
sex, race, oxygen saturation, respiratory rate, and initial peak flow at presentation) at the
hospital level. We have chosen these specific variables based on our prior research on this
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topic.26 In sensitivity analysis to assess the robustness of our findings, we will generate the
hospital-level composite concordance scores by using the ‘‘opportunity-based’’ method (i.e.,
the patient-level composite scores are summed at the hospital level).27 Complete case analyses
will be used for unadjusted analyses. Multiple imputation by using multivariate normal model
will be employed for the multivariate regression analyses to account for the variables with
significant missing data.28
8.3.2
Handling of missing values/censoring/discontinuations
Variables with substantial missing data will be dummy coded by using the missing indicator
method.29
8.3.3
Other
All tests will be 2-tailed, and P<0.05 will be regarded as statistically significant. All analyses
will be performed with Stata 13.0 software (StataCorp, College Station, TX) and SAS 9.3
software (SAS Institute, Cary, NC).
8.4
Sample size/power calculation
The target sample size is a total of 1000 patients hospitalized for acute asthma. The table
below shows approximate 95% confidence intervals for the proportion of patients with at least
one hospitalization for acute asthma in the past year. We anticipate approximately 55% of the
patients to have a hospitalization in the past year.4-6 Even if the percentage is somewhat lower
or higher, the target sample size (n=1000) will provide a 95% confidence interval of only 6
percentage points, which is a tight enough band for us to draw inferences from the results.
Table 8.4-1 Approximate 95% Confidence Intervals
Assumed frequency (%) (n=1000)
95% confidence interval (%)
40
37 – 43
45
42 – 48
50
47 – 53
55
52 – 58
60
57 – 63
65
62 – 68
70
67 – 73
9
Data monitoring and quality control
Chart abstractors at the site will have some medical training, with the vast majority being
physicians, nurses, or respiratory therapists. Abstractors will be trained by the EMNet
Coordinating Center, and then the abstractors will complete two practice charts, which will be
assessed versus a ‘‘criterion standard.’’ If an abstractor’s accuracy is less than 80% per chart,
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the individual will be retrained. Online tools (e.g. an extensive Manual of Procedures) will be
available for abstractors. Since all forms already have been adapted from forms used in prior
successful studies, 3-21 we are confident that the forms will function well across the 25
MARC-37 sites.
9.1
Site monitoring
The EMNet Coordinating Center will perform informal monitoring of sites, with the option to
perform a formal on-site audit, if warranted. The EMNet Coordinating Center also will assure
compliance monitoring. Monitoring activity will include reviews of the progress of the study
and compliance with protocol, SOPs and GPP guidelines.
9.2
Data recording and document retention
In all scenarios, the site investigators must maintain source documents for each patient in the
study, consisting of case and visit notes (e.g., hospital, ED, clinic medical records) containing
demographic and medical information, and the results of any other tests or assessments. No
information in source documents about the identity of the patients will be disclosed.
9.3
Data quality assurance
The EMNet Coordinating Center will assure database quality by reviewing the data entered
into the REDCap database by investigational staff for completeness and accuracy, and in
accordance with the data validation plan.
10
Limitations
This study has potential limitations. First, the study relies on medical record review for
description and quality assessment, and some of the apparent deficit of quality might be due
to under-documentation. However, a prior study demonstrated that the rates of assessments
and treatments for acute asthma by chart abstraction were similar to those by direct
observation, with κ coefficients ranging from 0.6 to 0.9.30 Second, this study examines only
patients who are hospitalized with acute asthma, and patients with mild asthma exacerbations
that do not result in hospitalization will not be assessed. Nevertheless, our focus is on the
characteristics and burden of patients with severe asthma exacerbation. Our data are likely
relevant to the hundreds of thousands of asthma patients hospitalized each year for asthma.
Finally, our sample is overly representative of academic and urban hospitals. Therefore, these
results may not represent acute asthma management practices in non-academic or rural
hospitals in the US. However, research at these sites is highly relevant from a policy
standpoint, because these institutions train the majority of physicians. These institutions thus
have a disproportionate impact on the quality of current and future asthma care.
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Ethical considerations
MARC-37 is an observational epidemiologic study without administration of any medication
or use of any device. Furthermore, patient-related data collection is done by the study of
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existing documents and medical records. Thus, this study qualifies as “minimal risk” and is
suitable for expedited IRB review.
Additionally, we will protect the privacy of subjects and confidentiality of the data through
the following measures: (1) each medical record number will be replaced with a study ID and
a key to the code stored in a password protected file at each study site (i.e., each site will
maintain the key to the code); (2) the coded data that will be entered into the REDCap
database do not contain identifiers that could be used by the EMNet Coordinating Center to
link the data to any individual subject; and (3) direct identifiers, such as medical record
number kept in each site, will be removed once all of the data are collected and analysis
performed on the de-identified data.
11.1
Regulatory and ethical compliance
Compliance with regulatory standards provides assurance that the rights, safety, and wellbeing of patients participating in non-interventional studies are protected (consistent with the
principles that have their origin in the Declaration of Helsinki) and that the study data are
credible and responsibly reported.
This study was designed and shall be implemented and reported in accordance with the
Guidelines for Good Pharmacoepidemiology Practices (GPP) of the International Society for
Pharmacoepidemiology (ISPE), the STROBE (Strengthening the Reporting of Observational
Studies in Epidemiology) guidelines, and with the ethical principles laid down in the
Declaration of Helsinki.
11.2
Informed consent procedures
The chart review study could not practicably be carried out without the waiver of consent,
given the difficulty in locating individuals who may have moved, the number of subjects and
cost and use of limited resources of locating individuals and sending letters and consent
forms, and the impact on the scientific validity of the study if we could use only data of
individuals from whom we were able to obtain informed consent. Furthermore, the coded data
that will be entered into the database will not contain personal identifiers. Each study site
requires an approval from the institutional review board of the protocol with waiver of
informed consent before data collection begins. Informed consent will be implied through
voluntary completion of the hospital site survey.
11.3
Responsibilities of the site investigator and IRB
Prior to initiation of the study, the site investigator is required to sign a protocol signature
page confirming his/her agreement to conduct the study in accordance with these documents
and all of the instructions and procedures found in this protocol and to give access to all
relevant data and records to the EMNet Coordinating Center, IRBs, and regulatory authorities
as required.
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Early termination of study
The study can be terminated at any time for any reason by the EMNet Coordinating Center.
The investigators may be informed of procedures to be followed in order to assure that
adequate consideration is given to the protection of the patient’s interests. The site
investigator will be responsible for informing their IRB about the early termination of the
study.
11.5
Publication of study protocol and results
Upon study completion and finalization of the study report, the results of this study will be
submitted for publication. Publications will comply with the International Committee of
Medical Journal Editors (ICMJE) guidelines. Authorship of the main results will be “on
behalf of MARC-37 investigators” with listing of one person from each site of appendix but
also on Pubmed as “collaborator”. The site investigator will decide who should be credited
from his/her site.
Study data will be held at the EMNet Coordinating Center at Massachusetts General
Hospital. Site investigators from participating sites may submit a proposal for a secondary
analysis of the data by using an online form (http://www.emnetusa.org/Coordinating_Center/SAPF.cfm). This online form will be posted on the EMNet
website and, when proposals are submitted, this will generate an automatic email to Dr.
Camargo (Principal Investigator, Massachusetts General Hospital) notifying him of the
submission. All secondary analysis proposals should state the hypothesis to be tested, the data
required, the analytic methods to be used, and the individual responsible for writing the
manuscript. Once the data for a specific secondary analysis have begun to be analyzed, the
expected time to completion of a manuscript will be 3 to 6 months. The study leadership will
retain the data and conduct the analysis according to specifications agreed upon with the
applicant. If necessary, funding for programming and statistical time may be requested from
the applicant or the team leader. If no manuscript has been completed within the projected
timeline, then the study leadership reserves the right to allow another investigator to approach
the same question, if a competing application has been received. With regard to secondary
manuscripts, there is no “on behalf” listing; it’s named authors only. More than one person
from each site could be listed.
11.6
Protocol adherence and amendments
Site investigators or other involved health care professionals will apply due diligence to avoid
protocol deviations. The protocol should be amended and updated as needed throughout the
course of the study. Any change or addition to the protocol requires a written protocol
amendment that must be approved by the principal investigator and the relevant IRB before
implementation. Amendments affecting only administrative aspects of the study do not
require formal protocol amendments or IRB approval but the IRB must be kept informed of
such administrative changes.
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References
1.
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review of economic evaluations of therapy in asthma. J Asthma Allergy. 2010;3:33-42.
2.
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Research adn Quality. http://hcupnet.ahrq.gov/. Accessed May 2, 2014.
3.
University HealthSystem Consortium. 2000 Adult and Pediatric Asthma Clinical
Benchmarking: Executive Summary. July 2001.
4.
Chandra D, Clark S, Camargo CA, Jr. Race/Ethnicity differences in the inpatient
management of acute asthma in the United States. Chest. 2009;135(6):1527-1534.
5.
Schatz M, Clark S, Camargo CA, Jr. Sex differences in the presentation and course of
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Griswold SK, Nordstrom CR, Clark S, Gaeta TJ, Price ML, Camargo CA, Jr. Asthma
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emergency department? Chest. 2005;127(5):1579-1586.
8.
Woodruff PG, Emond SD, Singh AK, Camargo CA, Jr. Sudden-onset severe acute
asthma: clinical features and response to therapy. Acad Emerg Med. 1998;5(7):695701.
9.
Cydulka RK, Emerman CL, Schreiber D, Molander KH, Woodruff PG, Camargo CA,
Jr. Acute asthma among pregnant women presenting to the emergency department. Am
J Respir Crit Care Med. 1999;160(3):887-892.
10.
Emerman CL, Woodruff PG, Cydulka RK, Gibbs MA, Pollack CV, Jr., Camargo CA,
Jr. Prospective multicenter study of relapse following treatment for acute asthma
among adults presenting to the emergency department. Chest. 1999;115(4):919-927.
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Emond SD, Woodruff PG, Lee EY, Singh AK, Camargo CA, Jr. Effect of an
emergency department asthma program on acute asthma care. Ann Emerg Med.
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Singh AK, Cydulka RK, Stahmer SA, Woodruff PG, Camargo CA, Jr. Sex differences
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Singh AK, Woodruff PG, Ritz RH, Mitchell D, Camargo CA, Jr. Inhaled
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Barr RG, Woodruff PG, Clark S, Camargo CA, Jr. Sudden-onset asthma
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15.
Boudreaux ED, Clark S, Camargo CA, Jr. Telephone follow-up after the emergency
department visit: experience with acute asthma. Ann Emerg Med. 2000;35(6):555-563.
16.
Emond SD, Reed CR, Graff LI, Clark S, Camargo CA, Jr. Asthma education in the
Emergency Department. Ann Emerg Med. 2000;36(3):204-211.
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Brenner BE, Chavda KK, Karakurum MB, Karras DJ, Camargo CA, Jr., Investigators
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Cydulka RK, Emerman CL, Rowe BH, et al. Differences between men and women in
reporting of symptoms during an asthma exacerbation. Ann Emerg Med.
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Radeos MS, Leak LV, Lugo BP, et al. Risk factors for lack of asthma selfmanagement knowledge among ED patients not on inhaled steroids. Am J Emerg Med.
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Weber EJ, Silverman RA, Callaham ML, et al. A prospective multicenter study of
factors associated with hospital admission among adults with acute asthma. Am J Med.
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Boudreaux ED, Emond SD, Clark S, Camargo CA, Jr. Race/ethnicity and asthma
among children presenting to the emergency department: differences in disease
severity and management. Pediatrics. 2003;111(5 Pt 1):e615-621.
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Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic
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Expert Panel Report 3 (EPR-3): Guidelines for the diagnosis and management of
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Tsai CL, Sullivan AF, Gordon JA, et al. Quality of care for acute asthma in 63 US
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McDermott MF, Lenhardt RO, Catrambone CD, Walter J, Weiss KB. Adequacy of
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13
Appendices
13.1
Appendix 1 Description of Quality Measures for Inpatient Acute
Asthma Care
Appendix Table. Description of Quality Measures for Inpatient Acute Asthma Care
Measure
Process measure
Treatment with inhaled
beta-agonists in hospital
Treatment with inhaled
anticholinergics in hospital
Numerator
Denominator
Level of
evidence
according
to EPR-3
Inhaled beta-agonist
given in hospital
Not given inhaled
anticholinergics in
hospital
Systemic corticosteroids
given in hospital
Not given
methylxanthines in
hospital
Oral corticosteroids
given at discharge
Initiation of inhaled
corticosteroid at
discharge
Patients being hospitalized with an
asthma exacerbation
Patients being hospitalized with an
asthma exacerbation
A
Patients being hospitalized with an
asthma exacerbation
Patients being hospitalized with an
asthma exacerbation
A
Patients being hospitalized with an
asthma exacerbation and discharged
Patients not on inhaled corticosteroids
prior to the hospitalization, and being
discharged
A
Treatment with antibiotics in
hospital
Continuation of inhaled
corticosteroid initiated at
discharge
Not given antibiotics in
hospital
Treatment with oral
antibiotics at discharge
Not given oral antibiotics
at discharge
Written asthma action plan
Written asthma action
plan given at discharge
Instruction for a followup asthma care
appointment within 1-4
weeks at discharge
Patients on inhaled corticosteroids
prior to the hospitalization, and being
discharged
Patients being hospitalized with an
asthma exacerbation. Exclusion:
infections that are generally of
bacterial origin (e.g., pneumonia,
otitis media, pharyngitis, and
sinusitis)
Patients being hospitalized with an
asthma exacerbation and discharged.
Exclusion: infections that are
generally of bacterial origin (e.g.,
pneumonia, otitis media, pharyngitis,
and sinusitis)
Patients being hospitalized with an
asthma exacerbation and discharged
Patients being hospitalized with an
asthma exacerbation and discharged
Treatment with systemic
corticosteroids in hospital
Treatment with
methylxanthines in hospital
Treatment with oral
corticosteroids at discharge
Treatment with inhaled
corticosteroid at discharge
Follow-up asthma care
appointment at discharge
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A
A
B
B
B
B
B
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Appendix 2 Data collection instruments
The MARC-37 study will use three instruments for data collection:
1)
Chart review log
2)
Site survey
3)
Chart review form
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