Patients with ALS Survey (PALS)
Greater Plains Collaborative
Coordination Center:
Department of Neurology,
University Kansas Medical Center
Kansas City, Kansas
913-588-6970
Protocol Version 1.0
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Table of Contents
1.0
Purpose of Research ........................................................................................... 3
2.0
Specific aim ......................................................................................................... 3
3.0
Prevalence, Background and Significance ........................................................... 3
3.1
Prevalence: ................................................................................................. 3
3.2
Background................................................................................................. 3
3.3
Greater Plains Collaborative (GPC) ............................................................ 4
4.0 Study design and rationale
5
4.1
Inclusion Criteria: ........................................................................................ 5
4.2
Exclusion criteria ......................................................................................... 5
4.3 Procedures ................................................................................................. 5
4.4 Recruitment………………………………………………………………………..5
4.5
Adverse events ........................................................................................... 5
5.0
Data Management and Case Report Forms ........................................................ 6
6.0
Biostatistical Approach: Outcome Measures, Data Analysis and Power .............. 6
7.0
Benefits and Risks of Research ........................................................................... 6
8.0
7.1
Known and Anticipated Risks ...................................................................... 6
7.2
Anticipated Benefits .................................................................................... 6
7.3
Privacy ........................................................................................................ 6
7.4
Informed Consent ....................................................................................... 6
7.5
Changes to Protocol ................................................................................... 6
7.6
Maintenance of Records ............................................................................. 6
7.7
Early Termination ........................................................................................ 6
7.8
Inclusion of women ..................................................................................... 6
7.9
Inclusion of minorities ................................................................................. 7
Data and safety monitoring plan .......................................................................... 7
8.1
9.0
Data Backup and Storage……………………………………………………… 7
Reference ............................................................................................................ 8
Appendix 1: GPC Survey
Appendix 2: Pioneer Recruitment Registry Online Consent
Appendix 3: Letter to subjects/instruction sheet
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1.0
Purpose of Research:
Our PCORI-funded Greater Plains Consortium (GPC) network is a powerful new
approach for utilizing electronic medical records (EMR) to collect and analyze clinical
data to improve patient care and outcomes. Patients with amyotrophic lateral sclerosis
(ALS) have a rapidly progressive neurodegenerative disorder and often experience
many functional changes between routine clinic visits. The ability to track changes in
functional status via surveys completed by the patient at home would help practitioners
better assess therapeutic interventions and maximize care. In addition a better
understanding of the demographic distribution of patients with ALS across the greater
GPC network, and differences in survey response rates in different ALS patient groups,
will be important as we design and implement new interventions to improve ALS patient
care. We developed a GPC survey which incorporates elements of a standard ALS
functional assessment tool, along with specific questions identified as being important in
a patient focus group meeting. In order to demonstrate proof of concept for our GPC
network, we plan to identify ALS clinic patients using our EMR and send our new GPC
survey. Response to this survey will demonstrate the feasibility of our GPC ALS network,
and the possibility of using a patient-reported survey to follow functional status in ALS
patients between clinical visits. This collaboration between the patient and their health
care provider team will broaden the tools available for improving clinical care.
2.0
Specific aims
Specific Aim #1:
We will demonstrate proof of concept of using the GPC network to track patient reported
outcomes. To achieve this aim, we will send a one-time survey to all ALS Clinic patients
at each of the GPC ALS network sites. We will utilize a scheme where patient surveys
will be given an unique identifier which can be associated back to the EMR to obtain
limited demographic data. However we will set up local ‘honest brokers’, to serve as a
firewall between the survey response data and data obtained from the EMR: final
analysis for all aims will be performed on de-identified data sets.
Specific Aim #2:
We will determine the clinical diagnosis and basic demographic characteristics of
patients in our GPC ALS network, and compare across GPC sites. We will compare
reposnders to our survey to non-responders. All data included in analysis will be deidentified from the EMR.
Specific Aim #3
We will determine response rates across different patient options for returning our
survey. We will compare response rates between different methods: individual email
links to surveys; online RedCap surveys, or mail in/in person response in clinic.
3.0
Prevalence, background
3.1
Prevalence:
ALS is a rare neuromuscular disorder with an estimated prevalence of 40 to 60 cases
per 1,000,000 and an incidence of 0.4 to 1.8 per 100,000 (Annegers, Appel et al. 1991).
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We estimate the ALS population in the US to be 12,000 to 24,000 with 5,000 new cases
diagnosed each year, based on a US population of 320,000,000.
3.2
Background
Amyotrophic lateral sclerosis is a progressive disease characterized by degeneration of
the voluntary motor system. It has a median age of onset of 55 years with a male
predominance of 1.5 to 1 (Norris, Shepherd et al. 1993). There is no racial or geographic
predisposition except for an increased incidence on the Marianas Islands of Guam. The
diagnosis is based on the El Escorial criteria (Brooks 1994; Brooks, Miller et al. 2000),
which define the key clinical and electrophysiologic signs of both upper and lower motor
neuron dysfunction. Weakness and atrophy begin either in bulbar or limb muscles and
spreads to contiguous myotomes. Respiration is usually affected late in the disease.
Patients with older age at onset, bulbar dysfunction, greater clinical disability, and poor
respiratory function have the poorest survival (Gubbay, Kahana et al. 1985; Eisen,
Schulzer et al. 1993). While 10-15% has a family history of ALS, the majority of cases
are sporadic (7). The majority of patients followed in multi-disciplinary ALS clinics will
have a clinical diagnosis of ALS. But motor neuron disorders exist on a spectrum from
pure upper motor disfucntion (primary lateral sclerosis, PLS), to mixed upper and lower
motor neuron dysfunction (ALS), to pure lower motor neuron involvement (progressive
muscular atrophy, PMA). In addition some patients followed in the ALS clinic will have
symptoms confined to the bulbar region, a condition termed progressibe bulbar palsy
(PBP). There is considerable overlap between these disorders, and some controversy
whether PMA and PLS may simply be varients of ALS. The prevalence of these other
motor neuron disorders are assumed to be low compared to ALS, but the actual
prevalence in the ALS clinics are not known.
ALS Scale - Revised (ALSFRS-R Functional Rating)
Functional rating scales have become the standard primary outcome measure for clinical
trials of neurodegenerative diseases including Parkinson’s disease, Huntington’s
disease, and Alzheimer’s disease. Functional scales predict disease progression and
measure activities of significance to patients. The ALS Functional Rating Scale
(ALSFRS) was designed to assess the ability of ALS patients to perform activities of
daily living and to detect functional changes during clinical trials(1996). Precedent for
using this scale in clinical trials stems from the only positive treatment trial of riluzole in
ALS, when a predecessor of the current ALSFRS-R, showed slower decline in treated
patients relative to placebo(Bensimon, Lacomblez et al. 1994; Miller, Bouchard et al.
1996). A revised version of the ALSFRS, the ALSFRS-R, encorporates questions about
respiratory function into the scale, improving its sensitivity, and has become the current
standard outcome measure for ALS studies(Cedarbaum, Stambler et al. 1999). The
ALSFRS-R is a quickly administered, by research personnel or study staff, (five minutes)
ordinal rating scale that assesses capability and independence in 12 functional activities.
These include six bulbar-respiratory functions, three upper extremity functions (writing,
cutting food, and dressing), and three gross motor functions (walking, climbing, and
turning in bed). Each activity is recorded to the closest approximation from a list of five
choices, scored 0-4, with the total score ranging from 48 (normal function) to 0 (no
function). The ALSFRS-R has been used extensively in previous clinical trials and
validity has been established by correlating ALSFRS-R scores with quantitative strength
testing and changes in strength over time(Gordon, Moore et al. 2007; Miller, Bradley et
al. 2007; Lauria, Campanella et al. 2009; Moviglia, Moviglia-Brandolino et al. 2012;
Sacca, Quarantelli et al. 2012; Beghi, Pupillo et al. 2013; Cudkowicz, van den Berg et al.
2013; Dorst, Cypionka et al. 2013; Shefner, Watson et al. 2013). The ALSFRS-R can
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also be used to follow disease progression in clinic. Limited studies have assessed
patient-reported versions of the ALSFRS-R(Montes, Levy et al. 2006; Kaufmann, Levy et
al. 2007). The ability to use a patient-reported tool like the ALSFRS-R to assess patient
function between clinic visits from the home would be a powerful new tool for clinicians
to monitor the effect of interventions including: medications, orthotic devices, and
respiratory or feeding support. In order to make this possible we developed a new
patient-reported survey which incorporates many of the key elements of the ALSFRS.
Greater Plains Collaborative Patient Reported Outcome Measures
The ALSFRS- R was sent to approximately twenty ALS patients throughout the Greater
Plains Collaborative region and their caregivers. They were asked if the scale was
difficult to understand; if there were items they felt should be dropped from the ALSFRSR or new items that should be included. There were 2 focus group conference calls
where the patients gave their opinion of the scale. Patient focus group recommendations
were that there needed to be some clarification in meanings of some of the words in the
ALSFRS-R, but overall the impression was that this instrument reflected the types of
functional limitations they experienced on a daily basis. There were also several items
they believed should be added to the ALSFRS-R: a question about pain; a question
about emotional liability; and a general non-demoninational question about faith. Our
new GPC survey follows the suggestions of the patient focus groups and modifies the
language of the ALSFRS-R and adds suggested items.
3.3 Greater Plains Collaborative (GPC)
The Greater Plains Collaborative (GPC) is a PCORNet Clinical Data Research Network
(CDRN) composed of 10 leading medical centers repurposing the research programs
and informatics infrastructures developed through Clinical and Translational Science
Award (CTSA) initiatives. Partners are the University of Kansas Medical Center (KUMC),
Children’s Mercy Hospital, University of Iowa Healthcare, the University of WisconsinMadison, the Medical College of Wisconsin, and Marshfield Clinic, the University of
Minnesota Academic Health Center, the University of Nebraska Medical Center, the
University of Texas Health Sciences Center at San Antonio and the University of Texas
Southwestern Medical Center. The GPC network brings together a diverse population of
over 10 million people across 1300 miles covering 7 states with a combined area of
679,159 square miles. Of these, over 6 million have significant data maintained in
electronic health records. This population covers the spectrum from primary care
networks serving rural and small communities to urban populations with significant
African American and Hispanic representation. ALS clinics exist at nine of the ten
medical centers in the GPC. The GPC selected amyotrophic lateral sclerosis (ALS) as
the rare disease for which we could readily access all patients across our network and is
working under the direction of Dr. Barohn to survey the population regarding their
willingness to engage in research and provide patient reported outcome measures.
Dr. Waitman (GPC principal investigator) is working with the informatics site leads to
tailor existing electronic medical record systems, data repositories based upon the i2b2
software developed through the National Center for Biomedical Computing at Partners
Healthcare System, data capture systems based on REDCap (Research Electronic Data
Capture) developed by Vanderbilt University, and governance processes to support
comparative effectiveness research in alignment with PCORNet objectives. The GPC
complements considerable investments in electronic health records by our healthcare
systems with existing NIH-funded technology (e.g., i2b2, REDCap) to provide a costeffective common data model that promotes data transparency and interoperability. This
includes:
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1. Collecting Patient Reported Outcome Measures (PROM) standardized measures
deployed using either EMR patient portals or data collection instruments for
existing registry and research management systems such as REDCap.
2. Configuring comparative effectiveness trial components directly in the EMR
(preferred) or integrate existing data capture and trial management systems.
Tailoring existing methods (a lightweight i2b2 plug-in) so that each site’s honest broker
can extract limited data sets composed of EMR and PROM and securely transfer them
to the GPC data store to support the conduct of the comparative effectiveness research
(CER) trial monitoring and analysis.
4.0
Study Design and Rationale
The study is a prospectively collected one-time survey (Appendix 1) that will be sent to
all ALS Clinic patients at the nine ALS sites within the GPC. We anticipate that each site
follows between 30-230 (depending on location) patients in the ALS Clinic. Each survey
will contain a cover letter explaining the survey, and why they are being asked to
participate, and instructions for comlpeting the survey.
4.1
Inclusion Criteria:
Any patient seen in one of the 9 particpating GPC network ALS Clinics within the last
two years.
4.2
Exclusion criteria
Any patient not willing to participate.
4.3
Procedures:
Each participant will receive a letter telling them about the upcoming survey and asking
for their participation approximately 1 month prior to the survey being distributed.
A cover letter describing the survey with instructions for completing the survey will be
sent to all qualifying patients seen at the nine GPC ALS Clinics. The survey will be sent
by email (depending on site requirements), through my chart (if the patient has signed
up), or by mail. Patients will have the following options for returning the survey: 1) for
patients with a current email address or they have registered through mychart, they can
follow a link embedded in their email to their individual survey; 2) patients with internet
access can go to a secure RedCap website to enter their unique survey identifier that
will take them to their individual survey; and 3) patients can elect to return the paper
survey by mail, or return it in person at their next clinic visit. In addition patients can
complete the surveys on-line or in person at their clinic visit. Two weeks after the
surveys have been distributed local coordinators from each site will call their own
patients to find out if their have received their survey, and answer any questions about
the purpose of the survey, or how to complete the survey.
4.4
Recruitment
Each of the nine GPC - ALS network sites will provide a list of patients with the ICD-9
code of 335.20, 335.24, or 335.29 seen in the ALS clinics within the last two years to the
local PI or study coordinator. The PI or study coordinator will confirm if these patients are
followed in their clinics, not deceased and otherwise rectify the list to be inclusive. The
information technology officer (ITO) will create a final list comprising the clinic ALS
patient lists, and possible patients identified in the EMR. After this list is rectified, a
letter will be sent to all study participants.
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4.5
Adverse events
This is a survey and we do not anticipate any adverse events from this study.
Participation is voluntary, and patients can chose not to participate.
5.0
Data management and case report forms
We will utilize a schematic for data flow where each site will have an honest broker (the
local ITO) who can extract limited data sets composed of EMR and GPC survey
response data and securely transfer them to the GPC data store to support the conduct
of the comparative effectiveness research (CER) outlined in this protocol. At each site
the lists of qualifying ALS clinic patients will each be given an unique identifier generated
for the GPC survey: each survey will have a unique identifier that will link to that patients
EMR. The local ITO will serve as honest broker, forming a firewall between the data
collection and analysis. Survey responses will be entered either electronically or
manually into the local database managed by the local ITO, and maintained in a
password secure REDCAP database on the local University secure IT network. We will
allow 3 months from distribution of the surveys for all survey responses to be completed.
When we are ready for analysis, the sponsor (University of Kansas Medical Center) will
approach the local ITO to retrieve the GPC survey data and selected EMR information
for the entire cohort which will be transmitted in a de-identified data set. The following
EMR data will be included for analysis: age, gender, race, ethnicity, living situation,
occupation, and years of education.
6.0
Biostatistical Approach: Outcome Measures, Data Analysis and Power
The goal of the GPC network survey is to provide proof of concept that we can utilize the
network to reach out to patients, and the patients will repsond: we will measure the
response rate to the survey as the primary study outcome metric and consider the study
successful if 50% of patients return the completed surveys. Basic descriptive statistics
will be used to describe the overall ALS clinic cohort: including basic demographics (age,
gender, race, ethnicity, living situation, occupation, years of education) and functional
burden as identified by survey response (clinical diagnosis, and functional status).
Investigations of participation response rates by site, demographics, GPC survey, and
by method of response (email versus mail) will be performed to determine which patients
are more likely to return a survey. We will perform simple comparison of binomial
proportions (participation/no participation) by these covariates with contingency table
analysis along with measures of association (e.g., odds ratios for 2 x 2 comparisons).
Analyses will be extended to the use of unconditional logistic regression analysis to look
at the joint effects of multiple covariates. Adjusted odds ratios (and 95% confidence
intervals) will be use to summary the magnitude of association between a covariate and
participation.
7.0
Benefits and Risks of Research
7.1
Known and Anticipated Risk
There are no known or anticipated risks from completing this survey. There is a minimal
risk that the firewall may be breached and the patients EMR would be released. To
protect against this risk all surveys will be given a unique identifier that can only be tied
to the EMR by the local honest broker (e.g. the ITO). Only de-identified data sets wil be
transmitted for analysis.
7.2
Anticipated Benefits
There is no direct benefit from participating in this survey. The ALS Clinic population as
a whole may benefit from more efficient and precise methods for tracking responses to
clinical interventions, thus improving overall clinical care.
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7.3
Privacy
Final data sets will be de-identified so no private information can be ascertained from
the analysis itself. There is minimal risk that the firewall may be breached.
7.4
Informed Consent
This study poses minimal risk to the patient. The consenting process will take via the
weblink or implied if the patient returns the survey to study personnel for entry into the
weblink.
7.5
Changes to Protocol
Changes in this protocol will be documented in the form of an amendment, and must be
approved by each study center IRB. Administrative changes (e.g., clarification of study
protocol, or change in method of a statistical analysis) do not require IRB approval, but
should be reported to the IRB.
7.6
Maintenance of Records
If the survey is returned, it must be kept onsite for seven years. If answered online, no
copies of the survey will be maintained.
7.7
Early Termination
All subjects are free to withdraw from participation in this study at any time, for any
reason.
7.8
Inclusion of women
The male to female ratio of ALS is 1.5:1. Therefore, the anticipated gender distribution is
approximately 60% male and 40% female. The majority are between 50 and 60 years
old. Every effort will be made to include women in this study, and we anticipate the
gender distribution in the study will be that of ALS.
7.9
Inclusion of minorities
There is no racial predisposition for ALS, and so we anticipate the racial mix will be that
of the western United States.
8.0
Data and safety monitoring plan
No specific data and safety monitoring plan is specified.
8.1
Data Storage and Backup
Hard copies of IRB approval will be stored at each of the nine GPC sites. The sponsor
(University of Kansas Medical Center) will maintain a copy each sites IRB approval.
Electronic data will be kept locally on each sites REDCAP system, per local IT protocols
for data integrity and back up.
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9.0
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