Remote Pulmonary Function Testing and Nurse Respiratory Health Coaching in Amyotrophic Lateral Sclerosis
Phase: NA
Conditions: ALS
Sponsor: Milton S. Hershey Medical Center

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HRP-591 - Protocol for 
Human Subject Research
Protocol Title:
Remote pulmonary function testing in amyotrophic lateral sclerosis (ALS)
Principal Investigator:
Name: Andrew Geronimo 
Department: Neurosurgery
Telephone: (717) 531-0003, x282576
E-mail Address: ageronimo@pennstatehealth.psu.edu
Version Date:
March 7, 2021
Clinicaltrials.gov Registration #:
NCT03214224
Important Instructions for Using This Protocol Template:
1.
Add this completed protocol template to your study in CATS IRB (http://irb.psu.edu) on the “Basic Information” 
page, item 7. 
2.
This template is provided to help investigators prepare a protocol that includes the necessary information needed 
by the IRB to determine whether a study meets all applicable criteria for approval. 
3.
Type your protocol responses below the gray instructional boxes of guidance language.  If the section or item is 
not applicable, indicate not applicable.
4.
For research being conducted at Penn State Hershey or by Penn State Hershey researchers only, delete the 
instructional boxes from the final version of the protocol prior to upload to CATS IRB (http://irb.psu.edu).  For all 
other research, do not delete the instructional boxes from the final version of the protocol.
5.
When making revisions to this protocol as requested by the IRB, please follow the instructions outlined in the Study 
Submission Guide available in the Help Center in CATS IRB (http://irb.psu.edu) for using track changes. 
If you need help…
University Park and other campuses:
Office for Research Protections Human Research Protection Program
The 330 Building, Suite 205
University Park, PA 16802-7014
Phone: 814-865-1775
Fax: 814-863-8699
Email: irb-orp@psu.edu
College of Medicine and Hershey Medical Center:
Human Subjects Protection Office
90 Hope Drive, Mail Code A115, P.O. Box 855
Hershey, PA 17033
(Physical Office Location: Academic Support Building Room 1140)
Phone: 717-531-5687
Fax number: 717-531-3937
Email: irb-hspo@psu.edu
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Table of Contents
1.0
Objectives
2.0
Background
3.0
Inclusion and Exclusion Criteria
4.0
Recruitment Methods
5.0
Consent Process and Documentation
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
7.0
Study Design and Procedures
8.0
Subject Numbers and Statistical Plan
9.0
Confidentiality, Privacy and Data Management
10.0
Data and Safety Monitoring Plan
11.0
Risks
12.0
Potential Benefits to Subjects and Others
13.0
Sharing Results with Subjects
14.0
Subject Stipend (Compensation) and/or Travel Reimbursements
15.0
Economic Burden to Subjects
16.0
Resources Available
17.0
Other Approvals
18.0
Multi-Site Research
19.0
Adverse Event Reporting
20.0
Study Monitoring, Auditing and Inspecting
21.0
Future Undetermined Research: Data and Specimen Banking
22.0
References
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1.0
Objectives
1.1
Study Objectives
The speciﬁc objective of this proposal is to utilize the practice of telemedicine via connected health 
devices to enable the guided performance of a remote pulmonary function test (rPFT) in the home.  The 
rationale for this study is to determine whether telemonitoring of respiratory health can help exceed 
standards of ALS care.
Part 1: Demonstrate the reliability of remote pulmonary function testing, performed via telemedicine, 
for monitoring respiratory function in patients with amyotrophic lateral sclerosis (ALS)
Primary Hypothesis: There is no difference in the results of PFT and rPFT for respiratory assessment of 
FVC and MIP.
Secondary Hypothesis:  The respiratory therapist, patient, and caregiver will express confidence in 
conducting the rPFT, as determined by surveys of procedure acceptance.
Part 2: Weekly remote pulmonary function testing (rPFT) and nurse respiratory health coaching 
(NRHC) in ALS telemedicine
This part randomizes subjects into two arms – both perform weekly rPFT testing and one receives 
monthly NRHC.
Aim 1: Clinically-meaningful benefit of weekly rPFT
Primary Hypothesis: Home respiratory assessment enables thresholds for non-invasive ventilation (NIV) 
recommendation to be met on average 30 days sooner when measured weekly compared to the 
standard 3-month interval.
Secondary Hypothesis: Determine the factors associated with adherence to weekly rPFT procedures.
Aim 2: The impact of NRHC on patient outcomes
Primary Hypothesis: Patient and caregiver teams in the NRHC arm report higher self-efﬁcacy in the 
respiratory management of the disease at 6 months compared to those in the non-NRHC arm.
Secondary Hypotheses: Patients in the NRHC arm report higher self-efﬁcacy at 12 months, experience 
less decline of respiratory-related quality of life and fewer respiratory complications compared to those 
in the non-NRHC arm.
1.2
Primary Study Endpoints
Part 1:  The primary endpoint is completion of a standard PFT and an experimental rPFT during a single 
clinic appointment.  At the endpoint, study outcomes will include:
1)
The best forced vital capacity (FVC) and maximal inspiratory pressure (MIP) results from that visit’s 
PFT
2)
The best FVC and MIP results from that visit’s rPFT
3)
Survey responses from study participants.
Part 2: The primary endpoint for Aim 1 occurs at the clinic visit following initiation of NIV.  At this time, 
participants will have had weekly measurements of FVC and MIP from self-administered rPFT 
procedures, as well as standard PFT assessments performed with the assistance of the respiratory 
therapist at approximately three-month intervals during standard in-person or telehealth clinic 
appointments.  The primary endpoint for Aim 2 will be the change in self-efficacy scores from baseline.  
Changes will be compared across arms.
1.3
Secondary Study Endpoints
In Part 2: All participants will undergo a training period for rPFT procedures, which entails weekly rPFT 
coaching by a member of the research team for the first four weeks.  To proceed with the remainder of 
the study, the participant team must demonstrate the ability to perform and transmit rPFT results to the 
research team during the 4th rPFT training session, and demonstrate FVC test results that are within 10% 
of the mean values achieved during the first three training sessions.  Training sessions will occur at 
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weeks 8 and 12 to monitor aptitude.   Changes in self-reported respiratory quality of life will be 
measured as part of procedures in Part 2.  Participants completing the study may be offered the 
opportunity to participate in a focus group on their experience in the study, which will be conducted via 
Penn State Health Zoom videoconferencing and have audio recorded.
2.0
Background 
2.1
Scientific Background and Gaps
Non-invasive ventilation (NIV) lengthens survival and improves QoL for patients with ALS.
According to the Quality Measurement Set put forth by the American Academy of Neurology (AAN), two 
parameters of high importance in ALS care are monitoring of respiratory function and management with 
NIV [Miller2013].   The practice parameter of the AAN regarding ALS care states that NIV is effective in 
prolonging survival and slowing the rate of respiratory decline [Miller2009].  NIV has been documented 
to have a positive effect on QoL in the areas of sleep quality, daytime sleepiness, physical fatigue, and 
depression [Butz2003].  NIV is recommended when a patient presents with either an FVC≤50% predicted 
or a MIP > -60 cm H2O [Miller2009].  It is recommended that PFTs be done at least once every three 
months, and that doctors discuss options for NIV support regularly.  
The multidisciplinary clinical model may not provide optimal management for patients with rapidly 
progressing respiratory symptoms.
Although disease course varies substantially, some patients experience rapid respiratory decline.  In 
prospective study of 38 newly diagnosed patients, half presented with chronic hypoventilation after one 
year, necessitating the introduction of NIV [LoCoco2006].   The authors suggest that efforts should be 
made to evaluate pulmonary function in these patients at least once every month.   Furthermore, it has 
been shown that early initiation of NIV at an FVC threshold of 65% predicted was associated with a 
significant increase in the median time from ALS diagnosis to death [Lechtzin2007].  The current practice 
of quarterly respiratory assessment may leave some individuals in danger of developing to untreated 
respiratory insufficiency or beginning treatment later than would be optimal or other more scientific 
wording.
Telemedicine has impacted other areas of neurology, but is understudied for efficacy in ALS.
The practice of telemedicine involves the delivery of medical care via long-distance and electronic 
communication between a health care professional and a patient or another health care professional.   
This type of intervention can expand medical coverage into underserved regions, while maintaining the 
high quality of care. Success with telemedicine in other areas of neurology, such as in the treatment of 
Parkinson's disease [Samii2006], epilepsy [Ahmed2008], and stroke [Demaerschalk2009], provide a 
framework for achieving positive outcomes.
It is largely unknown whether remotely-provided multidisciplinary care results in outcomes for ALS 
patients and their caregivers that are comparable to those achieved with traditional care.  A review by 
Hobson et al. identified 32 publications addressing telemedicine in ALS [Hobson2016], which concluded 
that patients are comfortable using the videoconferencing interface to discuss most concerns, they 
appreciated the reduced travel time and costs, and the use of telemedicine extended the period for 
which they received multidisciplinary care.   Some programs offered live interaction with providers as a 
way to delivered care to individuals in rural areas with no alternative treatment options [ALS-
Maine2010, Bedlack2014].   Other models utilized a traveling nurse to perform the assessment in the 
patient's home, which is stored and forwarded to the appropriate providers at the multidisciplinary 
clinic [Pulley2015, McClellan2013].  Others have taken on a more passive role, with monitoring of 
oximetry and non-invasive ventilation (NIV) data by a nurse led to fewer hospital visits, and higher 
treatment adherence [Pinto2010, Vitacca2010, Ashcroft2016].  
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Despite these results, Hobson concludes “There is limited evidence to recommend the use of 
telemedicine or telehealth in the case of patients with ALS.  Using telehealth as an alternative to clinic 
visits appears technically feasible but further research needs to establish its safety and effectiveness” 
[Hobson2016].   To address gaps in telemedicine care, randomized controlled clinical trials must be used 
to identify methods that can meet or surpass the standards of in-person assessment.
2.2
Previous Data
Preliminary work by our group as part of a pilot study assessing the benefits of ALS telemedicine has 
shown that the practice of live telemedicine is viewed favorably by ALS patients, caregivers, and 
multidisciplinary ALS team members, although less so by the latter group (Figure 1, [Morris2016, 
Geronimo2017]).  Overall, the three rater groups were concerned that the lack of physical contact 
lessened the ability for providers to deliver equal care.  This led us to identify and act upon one area of 
care that could be improved in telemedicine – assessment of breathing function.
Figure 1: Patient (P), caregiver (C), and health care provider (H) ratings of the ALS telemedicine pilot 
in four domains [Geronimo2017]. Circles containing an X mark the medians, thick lines span the ﬁrst 
to third quartile of data, with thin lines extending up to two times this range. Outliers are those small 
circles outside this range
From January to September 2018, the procedures for part 1 were completed in forty patients.  The main 
result was that the simulated remote assessment produced similar values of FVC and MIP compared to 
standard assessments (Figure 2).  In this sample, the specificity and sensitivity of FVC measurements 
were 100%, for MIP assessments was 89% and 82%, respectively [Geronimo2019].  The results of part 1 
indicate that rPFTs are accurate and acceptable measures of respiratory health.
 
Figure 2: FVC (Left) and MIP (Right) data from 40 subjects of the rPFT pilot study, comparing standard 
PFT measures to therapist-guided remote assessments. Four shaded quadrants are created by 
segmenting standard and remote tests by predeﬁned clinical thresholds.
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2.3
Study Rationale
The rationale for this study is to determine whether telemonitoring of respiratory health can help 
exceed standards of ALS care.
3.0
Inclusion and Exclusion Criteria
3.1
Inclusion Criteria
Part 1
Patients:
1)
Possess a diagnosis of definite, probable, probable laboratory-supported, or possible ALS by revised 
El Escorial research criteria [Brooks2000], or a diagnosis of primary lateral sclerosis (PLS, upper 
motor neuron involvement only) or progressive muscular atrophy (PMA, lower motor neuron 
involvement only).
2)
Be 18 years of age or older.
3)
Have a caregiver available to participate in the study
Caregivers:
1)
Be 18 years of age or older, of either gender.
2)
Be able and willing to provide informed consent.
Controls:
1)
Be 18 years of age or older, of either gender.
2)
Be able and willing to provide informed consent.
Respiratory Therapist
1)
Be a member of the Hershey Medical Center ALS multidisciplinary care team.
2)
Be able and willing to provide verbal informed consent after receiving a summary explanation of 
research (SER).
Part 2:
Patients:
1)
Possess a diagnosis of definite, probable, probable laboratory-supported, or possible ALS by revised 
El Escorial research criteria.
2)
Be 18 years of age or older.
3)
Have a caregiver available to assist with home PFTs or, in the opinion of the investigator, can 
perform home PFTs unassisted.
4)
Symptom onset within the last three years.
5)
Have a computer and home internet service sufﬁcient for engaging in telemedicine sessions.
6)
Have a second device capable of downloading the spirometer application from an app store 
(Android- or iOS-based smartphone or tablet).
Caregivers (not necessary to be enrolled if patient can perform home PFTs unassisted):
1)
Be 18 years of age or older, of either gender.
2)
Be able and willing to provide informed consent.
3.2
Exclusion Criteria
Part 1
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Patients:
1)
Cognitive impairment, as judged by the ALS clinic neurologist, that prevents participation in the 
study.
2)
Unable to perform pulmonary function testing with mouthpiece or with mask, as determined by one 
of the study investigators.
Caregivers: None
Controls: None
Respiratory Therapists: None
Part 2 imposes additional exclusion criteria for patients only.
Patients:
3)
Use of NIV or diaphragm pacer at time of obtaining informed consent.
4)
FVC ≤50% predicted
3.3
Early Withdrawal of Subjects
3.3.1 Criteria for removal from study
Participants may voluntarily withdraw from the study at any time.  The research team may also 
terminate the study if the participant does not meet the inclusion criteria or exhibits one or more 
of the exclusion criteria during the course of the study.  For part 2 of the study, participants may 
be removed if they exhibit non-compliance to study procedures.  Non-compliance is defined as 30 
days without submission of an rPFT report if still eligible for rPFT reporting, or 3 months without a 
nurse coaching session if in the nurse coaching arm.
3.3.2
Follow-up for withdrawn subjects
The research team will follow up with withdrawn subjects to collect the research equipment.  If 
the participant agrees, they will be given the endpoint assessment to document their reason for 
withdrawal.  They may be asked to participate in a future focus group on subject experience in 
the study.  There will be no additional follow-up.  The withdrawn subjects may be replaced by 
another patient and caregiver from the recruitment waitlist.
4.0
Recruitment Methods
4.1
Identification of subjects
Potential patient participants will be identified by study staff of the Penn State Hershey ALS center at 
the time they are seen for routine visits to the Penn State Hershey ALS Clinic, or based on their 
responses to recruitment letters (see below).   Potential subjects may also learn of the study by a flyer 
posted in the ALS clinic area.  Practice control participants will be recruited from clinical staff.  
Respiratory therapists sought for participation in the study will be those providing respiratory therapy 
services to ALS patients in the clinic on the date of the study.  The study will be listed on StudyFinder.
4.2
Recruitment process
Potential patients and caregivers will be approached by study staff of the Penn State Hershey ALS center 
at the time they are seen for routine in-person or telehealth visits to the Penn State Hershey ALS Clinic.  
In addition, a letter will be sent via mail or email to patients of the Penn State Hershey Medical Center 
ALS clinic, as well as those who are registered with the Greater Philadelphia chapter of the ALS 
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Association.  A flyer will be posted in the clinic area informing patients of the study.  Study information 
and contact information will be posted on Studyfinder.
Interested individuals will respond to a member of the study team who will follow up as in Section 4.4.
Practice control participants will be recruited from clinical staff by members of the study team.
Respiratory therapists will be approached by study staff prior to their first rPFT administration so that 
they may be delivered the SER and give verbal consent.
4.3
Recruitment materials
Potential patient participants may be mailed (see “Recruitment Letter” in Recruitment Materials) or 
emailed (see “Email Recruitment Letter” in Recruitment Materials) a recruitment letter.  There will also 
be a flyer for the study posted within the clinic area (see “Study Flyer” in Recruitment Materials).
4.4
Eligibility/screening of subjects
Before enrolling prospective participants, we will contact the potential them by phone, email, or in 
person. For those individuals who are Hershey Medical Center patients, we will ask for their consent to 
access their medical record to confirm certain inclusion and exclusion criteria.   For potential 
participants who are not treated at the Hershey Medical Center, we will request that they release 
medical records to us from their doctor.  These will be reviewed by the study physician to confirm the 
diagnosis of ALS and other inclusion/exclusion criteria.
We will confirm that they and their caregiver are aware of the study requirements and are willing to 
complete the study procedures according to the procedures described (see “Screening questionnaire” in 
recruitment materials).  This form addresses the remaining inclusion and exclusion criteria. In it, we will 
ask the patient if they anticipate any issues relating to performing spirometry or lack or devices or 
adequate internet access to participate (in the case of Part 2).  They will be directed to an online 
internet speed test to ensure sufficient connection speed.  We also ask if the caregiver anticipates they 
will be able assist in administering the procedure.   If a caregiver is not available, a patient may be 
enrolled in the study if the investigator judges that they have the capacity to perform home PFTs 
unassisted. If at any point in the study a patient enrolled without a caregiver is no longer able to 
perform the home tests without additional assistance, a caregiver must be enrolled to aid home PFT 
administration, or the patient will be exited from the rPFT portion of the study.
Eligibility of respiratory therapists will be determined by their role in the Hershey Medical Center ALS 
clinic as well as their verbal consent to participate in the study.
5.0
Consent Process and Documentation 
5.1
Consent Process 
 
5.1.1
Obtaining Informed Consent
5.1.1.1 Timing and Location of Consent
A member of the study team will review the informed consent documents with the 
participants and receive their written consent to participate in the study.  This 
consent procedure will take place only after initial screening procedures have been 
completed.  This will take place either at the Hershey Medical Center ALS clinic, 
over the phone, or using the telemedicine interface between the clinic and the 
patient’s home.
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Prior to any phone consent, participants will be provided with a physical or 
electronic copy of the informed consent document.  The researcher attesting to the 
appropriateness of the consent process will complete the Phone Consent 
Signature Page.  The patient will mail back the signed consent forms, and the 
member of the research team who explained the research will attach the 
completed Phone Consent Signature Page to the consent forms with the original 
signatures of the patient and LAR. The study team will then send the patient and 
LAR a copy of their signed consent form and the Phone Consent Signature Page for 
their records.  Once the original signed documents are received by the study team, 
the participant may begin research procedures.
A member of the study team will deliver the summary explanation of research 
(SER) to participating respiratory therapists before their first clinical interaction in 
this study.  The SER will be delivered at the Hershey Medical Center ALS Clinic.
5.1.1.2 Coercion or Undue Influence during Consent
Patients will be informed that the treatment they receive for ALS will not be 
affected by their choice to participate in the study.  Explanation of the study and 
obtaining consent will be performed by a member of the research team who is not 
part of the clinical care team.
5.1.2
Waiver or alteration of the informed consent requirement
Partial waiver of consent is requested for pre-screening purposes.
5.2
Consent Documentation
5.2.1
Written Documentation of Consent
We will verify that we are using the most current IRB-approved version of the study specific 
consent form and that the consent form is in language understandable to the subject. Whenever 
possible, the consent form will be provided to the subject in advance of the consent discussion. 
A member of the research team will review the informed consent documents with the 
prospective participants and receive their written consent to participate in the study described 
in this protocol.  If performed over the phone or telemedicine interfaces, participants will sign a 
physical copy of the form and mail/email it to the research team.  The patient and the caregiver, 
if available, will sign their own consent forms.  This consent procedure will take place either in 
the ALS Clinic or over the telemedicine interface between the clinic and the patient’s home.  
Written documentation of consent will be delivered after participants have been given an 
overview of the study's goals, procedures, risks, and benefits.   Participants will receive a copy of 
the consent after it has been signed and dated by the person explaining the study. 
5.2.2
Waiver of Documentation of Consent (Implied consent, Verbal consent, etc.)
Verbal consent will be obtained by the respiratory therapist participant before their first study 
session.
Verbal consent will also be obtained by participants via telephone to ask screening questions.
5.3
Consent – Other Considerations 
5.3.1
Non-English Speaking Subjects
Non-English speaking subjects will not be enrolled.
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5.3.2
Cognitively Impaired Adults
5.3.2.1 Capability of Providing Consent
The physician investigator will determine whether an individual is capable of 
providing informed consent. Cognitively impaired patients will not be enrolled in 
this study.
Due to disease progression, some subjects may not be able to physically sign the 
consent form, regardless of cognitive status thereby requesting LAR signature.
5.3.2.2 Adults Unable To Consent
The procedure outlined in HRP 013, “SOP: Legally Authorized Representatives, 
Children, and Guardians” will be followed to determine the legally authorized 
representative capable of providing informed consent. Written informed consent 
from the subject’s LAR will be obtained before any study procedures take place.
5.3.2.3 Assent of Adults Unable to Consent
Subjects who are unable to sign the consent will be asked to provide verbal assent, 
which may be provided using an assistive communication device.
5.3.3
Subjects who are not yet adults (infants, children, teenagers) 
5.3.3.1 Parental Permission
N/A
5.3.3.2 Assent of subjects who are not yet adults
N/A
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
6.1
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
Check all that apply:
 
Not applicable, no identifiable protected health information (PHI) is accessed, used or 
disclosed in this study. [Mark all parts of sections 6.2 and 6.3 as not applicable]
Authorization will be obtained and documented as part of the consent process. [If this is the 
only box checked, mark sections 6.2 and 6.3 as not applicable]
Partial waiver is requested for recruitment purposes only (Check this box if patients’ medical 
records will be accessed to determine eligibility before consent/authorization has been 
obtained). [Complete all parts of sections 6.2 and 6.3]
Full waiver is requested for entire research study (e.g., medical record review studies). 
[Complete all parts of sections 6.2 and 6.3]
Alteration is requested to waive requirement for written documentation of authorization 
(verbal authorization will be obtained). [Complete all parts of sections 6.2 and 6.3]
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6.2
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
6.2.1
Access, use or disclosure of PHI representing no more than a minimal risk to the privacy of the 
individual
6.2.1.1 Plan to protect PHI from improper use or disclosure
Information is included in the “Confidentiality, Privacy and Data Management” 
section of this protocol.
6.2.1.2 Plan to destroy identifiers or a justification for retaining identifiers 
The identifiers collected in the study and stored on REDCap will be maintained until 
the completion of the study, including analysis, and dissemination of results.  Email 
addresses and phone numbers may be retained for those participants who are 
interested in participating in future research studies.
6.2.2
Explanation for why the research could not practicably be conducted without access to and 
use of PHI
Certain PHI is used to maintain contact with the research subject though phone, mail, or email.  
Other PHI are variables related to the analysis of the study, such as date of birth, diagnosis, and 
gender.  Voice recordings of the subject during coaching sessions will be used to assess quality 
and consistency of NRHC procedures.  Voice recording of post-study focus groups will allow for 
easy transcription for analysis.
6.2.3
Explanation for why the research could not practicably be conducted without the waiver or 
alteration of authorization
In order to be able to screen participants, we will need to access their medical record, either 
through the Hershey Medical Center EMR or through the release of records from an external 
care provider.  We will access patients’ medical records for the purpose of confirming the 
diagnosis of ALS before we admit them into the study and obtain consent.  In order to contact 
patients, to describe the study and schedule the study visit, we will need access to phone 
numbers and email.  Additionally, in the case of Study 2, we will need to know the patient’s 
address to be able to ship the rPFT kit.
6.3
Waiver or alteration of authorization statements of agreement
Protected health information obtained as part of this research will not be reused or disclosed to any 
other person or entity, except as required by law, for authorized oversight of the research study, or for 
other permitted uses and disclosures according to federal regulations. 
The research team will collect only information essential to the study and in accord with the ‘Minimum 
Necessary’ standard (information reasonably necessary to accomplish the objectives of the research) 
per federal regulations. 
Access to the information will be limited, to the greatest extent possible, within the research team. All 
disclosures or releases of identifiable information granted under this waiver will be accounted for and 
documented.
7.0
Study Design and Procedures
7.1
Study Design
Part 1: This is a self-controlled study where each participant will be administered a standard of care PFT 
for measurement of FVC and MIP, as well as an rPFT, separated by at least an hour, for measurement of 
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experimental FVC and MIP.   The rPFT is guided by a respiratory therapist in another room, utilizing the 
telemedicine interface of the Hersey ALS clinic and devices for measuring FVC and MIP (Error! Reference 
source not found.). 
Figure 3: Tools for remote pulmonary testing.  Left: Air Smart Spirometer and turbine. Right: respiratory 
pressure meter and mouthpiece.
Part 2:  This is a two-arm, randomized study to determine 1) whether weekly monitoring of respiratory 
function can lead to timelier initiation of NIV and 2) whether structured nurse coaching leads to 
improved self-efficacy for managing disease and better maintenance of respiratory health.  For enrollees 
in both arms, standard FVC and MIP measurements obtained approximately every three months by the 
respiratory therapist during ALS Clinic are supplemented with self-administered rPFTs performed 
weekly.  To train the participant in the performance of rPFTs, a member of the research team will be 
present either in person or virtually to guide the patient and caregiver in the appropriate use of the 
equipment during the first four weeks of the study.  Enrollees in the NRHC arm will additionally receive 
monthly coaching with the study nurse via telehealth.  Approximately 5% of NRHC sessions will include 
audio recordings that will be evaluated by a second clinician nurse for quality and consistency.
rPFT protocol
Two devices are used to measure respiratory function:
1)
Air Smart Spirometer, NuvoAir AB
The following information is paraphrased from the user manual, which is included in the “devices” page 
of the protocol. 
The Air Smart Spirometer measures the forced vital capacity (FVC) in a forced expiratory maneuver. The 
Air Smart Spirometer is intended to be used by:

Healthcare professionals trained to perform spirometry tests on patients. 

Adults trained by healthcare professionals or through self-learning who understand how 
to perform a high quality spirometry test.
The Air Smart Spirometer works iOS and Android devices.  The Air Smart Spirometer has a built-in 
battery designed to function for at least 2 years or 1 000 single tests. The Air Smart Spirometer is 
designed to work with disposable and single use FlowMir® turbines. When performing a spirometry test, 
the user exhales into the turbine. The airflow generated sets a rotor in motion. The Air Smart Spirometer 
Air Smart spirometer and mouthpiece
Pressure gauge and mouthpiece
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registers the speed of the spinning rotor, converts it and transfers the data to the smartphone with the 
Air Smart Spirometer app.
The study subject will conduct 3-5 spirometry maneuvers to generate a forced vital capacity using the 
spirometer and associated application.  Subjects may use the "Home Monitoring" version of the app, 
which requires the user to enter their date of birth, height, gender, and ethnicity.  Alternatively, the 
"Clinical Trial" version of the application may pair the subject's smartphone to a cloud database hosted 
by Nuvoair using a subject-specific code.  The coordinator will enter date of birth, height, gender, and 
ethnicity into the database, to which all spirometry recordings made by the subject will be synced.   
2)
NIF Meter NS 120-TRR, Instrumentation Industries
The following information is paraphrased from the user manual, which is included in the “devices” page 
of the protocol.
“The Instrumentation Industries, Inc. Negative Inspiratory Force (NIF) Meters are devices used to 
measure and monitor patient inspiratory effort. During use the NIF Meter is attached to the patient 
airway at a point that provides optimal readings of patient respiratory effort.”
During each guided rPFT administration, a member of the research team and/or respiratory therapist 
will guide the patient and caregiver through three valid maneuvers of the FVC and MIP tests. The 
participants prepare the spirometer by connecting it to the tablet and opening the associated 
application. The patient is told to sit as upright as possible for the measurement of FVC. They will be told 
that to do this they will 1) inhale maximally, 2) exhale as hard and fast as possible, and 3) continue to 
exhale until indicated by the therapist. The researcher will also demonstrate this procedure to the 
patient. The caregiver applies nose clips to block airﬂow through the nose, holds the turbine of the 
spirometer to the patient’s mouth and performs three repetitions of this sequence, with periods of 
relaxation between testings.  Testing is repeated until three valid maneuvers are achieved. The 
application on the tablet computes the FVC and percentage predicted value, the best of which is 
retained.
To perform the MIP test, the participant inserts the mouthpiece into the pressure meter. The patient is 
told they will be asked to draw breath in as quickly and powerfully as possible, for at least one second. 
The researcher tells the caregiver to place a ﬁnger over the valve outlet so that no air ﬂows through the 
mouthpiece during inhalation. Nose clips will be used. The patient performs three repetitions of this 
task.  The maximal negative pressure from a valid run is recorded.
Each piece of reusable equipment will be labeled with an identification number.  A log of all loaned 
materials will be maintained by the researchers.  This log, included in the supporting documents, will be 
maintained on REDCap.  Before delivery of the system to the study participant, each piece of equipment 
will be inspected and tested.  This study will not collect prior medical therapy relevant to the use of the 
device.  There are no restrictions on medicines or therapies used by the participants in this study.
Randomization (Part 2 only)
An unblinded blocked minimization method will randomize participants based on demonstrated factors 
affecting prognosis [Chio2009]. These include: time since diagnosis, age at consent, most recent FVC, 
and FVC slope from up to the previous year, if available.
NRHC protocol (Part 2 only)
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Nurse Respiratory Health Coaching - The NRHC intervention follows the “teamlet” model described by 
Bennett et al. [Bennett2010], made up of the research coordinator who performs respiratory testing, 
and the nurse practitioner using an ALS-tailored variant of the GROW model.  5 percent of NRHC 
sessions will undergo audio recording and be reviewed by a nurse-researcher on the study team.

Goal setting - Discuss patient-driven goals for the session as well as for short and long term 
respiratory management for the patient/caregiver dyad.

Reality Check - Explore current situation. Review PFT results and answers to the respiratory 
questionnaire.  Share information and gently challenge assumptions that may present barriers 
to goal attainment.

Options - Identify options and alternative strategies, including NIV, Cough Assist, Nebulizer, and 
Breath Stacking. Discuss patient and system barriers to pursuing these options.

Wrap-up - Coach dyad towards implementing endorsed plan with a focus on trouble-shooting 
barriers and enhancing facilitators to successful implementation. Address what is to be done 
and by whom.
Those randomized to the coaching arm will receive brief coaching checkups from another nurse on the 
study team who is not the coach.  These will occur during the 4th and 8th months after randomization, 
and at study exit.  The nurse performing the checkup will guide the participant to reflect on the coaching 
process, using prompts provided in the Focus Group template.  Coaching checkups will be by phone or 
via Penn State Health Zoom videoconferencing. Audio of these sessions may be recorded.
Focus groups (Part 2 only)
Focus groups may be convened comprised of subjects who have completed the study.  Focus groups will 
ask subjects to reflect on their experiences in the study regarding the use of technology, nurse coaching, 
and any behavioral changes observed.  Focus groups will be conducted either at the location of the 
Hershey ALS Clinic or via Penn State Health Zoom videoconferencing. Audio recordings of the focus 
groups will be captured.
7.2
Study Procedures
7.2.1
Part 1
On or before the date scheduled for Study 1, a member of the research team who is not part of 
the ALS clinical team will describe the procedures and receive written informed consent from 
the patient and caregiver dyad, as well as the respiratory therapist.  The participant team 
undergoes the initial in-person pulmonary function testing, followed 2-3 hours later at the end 
of the clinical visit by the rPFT.  rPFT administration is described in Section 7.4.2.  For roughly 
half of the enrolled participants, the order of assessments is reversed.  Following the study 
procedures, the therapist and patient/caregiver dyad will complete a survey concerning the ease 
of use and confidence in the rPFT assessment.
Part 1 includes the recruitment of up to 20 practice control participants for validation of the 
study procedures.  They will perform the same procedures as the patient and caregiver, in 
conjunction with the respiratory therapist.
7.2.2
Part 2
Following consent, the researcher will collect demographic and clinical information: date of 
birth, gender, time since symptom onset, ALSF Functional Rating Scale - Revised, PFT history, 
and region of symptom onset. The researcher will guide the subject through completion of the 
respiratory health questionnaire and self-efficacy assessment.  
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Subjects consented on the day of their in-person clinic visit will be sent home with an rPFT kit 
and scheduled for weekly training appointments with a member of the research team.  For 
patients consented remotely, the research team will ship a kit and schedule them for weekly 
training appointments.
The weekly schedule following the first site visit at week 0 is shown in Error! Reference source 
not found.. Weekly training sessions will be guided through the telehealth interface by a 
member of the research team.  If by the 4th training session the participant is able to complete 
rPFT procedures without guidance as determined by the researcher-completed aptitude 
assessment, and achieve an FVC result within 10% of the average value from the first three 
sessions, the participants will be randomized to one of the two study arms.
Patients may be enrolled without a caregiver available if the investigator determines that the 
patient is able to perform the home breathing tests without additional assistance.  The patient’s 
ability to perform these tests solo will be reviewed at a minimum interval of successive clinic 
visits.  If they are no longer able to perform the home tests without additional assistance,  a 
caregiver must be enrolled aid home PFT administration, or they will be exited from the rPFT 
portion of the study.  Caregivers enrolled part-way into the study will receive training on 
administering rPFTs at that time.
rPFT arm: Subjects will continue to self-administer rPFTs every week.  A research team member 
will schedule rPFT training appointments at weeks 8 and 12 order to re-assess aptitude.  rPFT 
procedures are not performed during weeks in which a clinical appointment occurs.   Subjects 
will complete the following patient-reported outcomes:

Respiratory health questionnaire (monthly) - The questionnaire contains three Patient-
Reported Outcomes Measurement Information System (PROMIS) sub-scales on Dyspnea 
Characteristics (5 items, [PROdc2016]), Dyspnea Functional Limitations (10 items, 
[PROdfl2016]), and Sleep Related Impairment (8 items, [PROsri2016]). The PROMIS sub-
scales, all of which utilize Likert-type scaling, will be summed as composite scores, with 
higher numbers indicating poorer quality of life. Also included are seven questions 
regarding respiratory complications experienced in the previous month. 

Self-efficacy assessment (quarterly) - The self-efﬁcacy assessment contains questions 
from the PROMIS item banks on Self-Efﬁcacy for Managing Symptoms (9 items, 
[PROms2017]), Self-Efficacy for Managing Social Interactions (5 items, [PROsi2017]), and 
Self-Efficacy for Managing Medications and Treatments (4 items, [PROmt2017]).  These 
assessment tools, designed for use in chronic conditions, are scored as an average of 
individual components on a 1-5 scale.

ALS-Specific Quality of Life (quarterly) – Brief Form [Felgoise2018] – 20 questions in 5 
domains encompassing quality of life.  If the subject has completed this document in the 
last 30 days as part of clinical care, we may access this data from their chart.
rPFT + NRHC arm: In addition to the rPFT schedule described above, subjects randomized to the 
NRHC arm will begin monthly coaching sessions, with the first session scheduled as close as 
possible to the randomization date (week 4). These coaching sessions will take place over the 
ALS clinic telehealth interface and will last up to 30 minutes.  Coaching sessions will end at the 
completion of the 5th study session, with approximately 12 sessions per subject.  Five percent of 
total sessions (20 subjects  12 sessions   5% = 12 sessions) will have audio recorded.  Audio 
recordings are collected for review of quality and consistency of NRHC interactions by a second 
nurse member of the study team.
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Coaching checkups will be initiated by a nurse member of the study team who is not involved in 
patient coaching. These will occur at months 4 and 8 after randomization into the rPFT+NRHC 
arm and at study exit.  These will last 15-30 minutes each.  
If a subject records an FVC ≤50% predicted or a MIP > -60 cm H20, the researcher will forward 
the test report to the ALS clinical team, including nurse, respiratory therapist, and neurologist. If 
the decision is made to initiate NIV, the ALS clinic physician will provide an order, and the ALS 
clinic nurse will arrange for initiation of in-home NIV via a third-party vendor according to usual 
standards of care.  At the initiation of NIV, the subject stops rPFT procedures and returns the 
study equipment.  The remaining procedures continue through the end of the study period. The 
subject can also opt to end the study at any time.
Figure 4: Timeline of study interventions and outcomes. The primary outcome of Aim 1 is the time 
difference between ﬁrst identiﬁcation of NIV need and the next standard clinic visit, (∆). An example ∆ 
of 60 days is shown following threshold crossing indicated by the dotted vertical line. The outcomes of 
the second aim are monthly respiratory questionnaires and self-efﬁcacy assessments completed in 
clinic.
When the subject has completed all study procedures or withdrawn from the study, they may 
be asked to participate in a focus group which will have them reflect on their experiences in the 
study regarding the use of technology, nurse coaching, and any behavioral changes observed.  
7.3
Duration of Participation
Part 1: The study procedures, including screening, consent, assessment, and survey, are expected to 
take 45 minutes.  Administration of the simulated PFT with patient participants will be performed on the 
day of a scheduled clinic visit.
Part 2: Patient participants will be enrolled for approximately one year.  During this time, patients will 
engage in approximately five standard PFT assessments during in-person or telehealth clinic activities, 
requiring no additional time commitment.  Participants will also complete approximately 47 rPFTs, each 
taking 10-30 minutes to complete, depending on level of experience.  The respiratory questionnaire and 
the self-efficacy assessment each take approximately 10 minutes to complete.  Finally, those in the 
NRHC arm will receive up to 12-30 minute coaching sessions and 3-30 minute coaching checkups.  
Patients receiving nurse coaching can expect a total time commitment of approximately 26.5 hours, and 
those in the non-coached group can expect 19 hours of time spent on study procedures.  Caregivers may 
be enrolled for the same period or for a shorter period depending whether one is available and needed 
at the initiation of study procedures.
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8.0
Subject Numbers and Statistical Plan
8.1
Number of Subjects
Approximately (but no more than) 123.  We will enroll 40 patient/caregiver teams for Part 1 and up to 
60 patient/caregiver teams for Part 2 to achieve 40 pairs completing procedures for Part 2.   
Participants in the two studies may overlap.  Up to 20 practice control participants may be recruited for 
Part 1.  Up to three respiratory therapists will also be recruited for these studies.
8.2
Sample size determination
Our sample size is predetermined based on our subjective ability to recruit patients within the time 
frame of the study. Power analysis was based on studies of FVC decline. Lo Coco et al., [LoCoco2006], 
showed that 50% of study participants dropped below 50% predicted FVC in one year. Given that our 
exclusion criteria for Part 2 will reject many of the 37% of individuals in their study who were “slow 
progressors,” we estimate that 75% of patients enrolled in our study will meet the respiratory criteria to 
recommend NIV. This results in a sample size per arm of n=15, which provides 80% power to detect a 
difference in mean outcome between the two groups if the effect size is found to be 0.95.  
Assuming a monthly change in FVC of 3.5±3.4% found by Schiffman et al. [Schiffman1993], we 
conducted 10,000 Monte-Carlo simulations of 40 participants declining at this rate for 12 months. Half 
were sampled once every three months, and half were sampled every month. 80.6±6.3% of simulated 
participants met the requirements for NIV recommendation, in roughly equal proportions across groups. 
The average FVC at recommendation was 47.0% predicted in the experimental group, and 43.4% 
predicted in the control group. The effect size of the difference in FVC between groups was .964±.343. 
8.3
Statistical methods
Part 1:  The primary hypothesis is that there is no difference in the results of PFT and rPFT for respiratory 
assessment of FVC and MIP.  We will use a paired sample t-test to determine if the mean test results are 
comparable between the standard and experimental treatments.  We will conduct a qualitative analysis 
to determine whether the patient, caregiver, and therapist determine the rPFT to be an effective way to 
conduct tests of breathing function.
Part 2: Aim 1 will be analyzed to determine if the study date of NIV initiation is at least 30 days sooner 
based on rPFTs compared to standard clinic PFTs. This will be done using a non-parametric two sample 
test of means, the Wilcoxon-Mann-Whitney rank sum test.  For analysis of Aim 2, a linear mixed effects 
model will be used to analyze the change from baseline between study groups of self-efﬁcacy scores and 
respiratory health [Verbeke2000]. The effect size will be quantiﬁed from the model using the difference 
in means between the groups with their associated 95% conﬁdence intervals.
9.0
Confidentiality, Privacy and Data Management 
Please see HRP-598 Research Data Plan Review Form
10.0 Data and Safety Monitoring Plan
N/A
11.0 Risks
The risks posed to subjects in the study will be no different than those presented during standard of care 
administration of pulmonary function testing. In addition to guidance from the research team, those 
participating in remote assessments will be required to have a caregiver present to aid the patient in case 
assistance is required. 
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Loss of confidentiality is a risk of this study, but steps are taken to project the participants' identities. Personal 
information, clinical assessments, test results, and survey responses will be labeled with a participant code 
assigned by REDCap and stored in this database.  All data containing PHI will be collected either from the 
electronic medical record or in person.  Data transmitted through the Air Smart Spirometer app will be labeled 
with the user’s initials, gender, date of birth, and height, end ethnicity.  Audio from telemedicine interactions 
during nurse coaching interventions may be stored on REDCap for review by a member of the research team. 
Video from telemedicine interactions and focus groups will not be stored.
12.0 Potential Benefits to Subjects and Others
12.1
Potential Benefits to Subjects
Participants in Part 2 may benefit from timelier recommendation of NIV support.
12.2
Potential Benefits to Others
This knowledge gained by this study may benefit those who are managed remotely using telemedicine.  
This will enable virtual care to be more equivalent to in-person care.
13.0 Sharing Results with Subjects
Participants will be informed of the results of their breathing tests at each visit.  The respiratory therapist and 
nurse clinician will be responsible for making appropriate recommendations based on those results, and 
following up with the neurologist for NIV recommendation if necessary.
Participants will not be informed of overall study results unless they request it.  Study results include the public 
presentation of research at academic conferences or through peer-reviewed journals.  
14.0 Subject Stipend (Compensation) and/or Travel Reimbursements
There will be no compensation in Part 1.  For Part 2, the patient participant will be compensated $10 per month 
they are in the study, capped at a total compensation of $120.  
15.0 Economic Burden to Subjects
15.1
Costs 
Subjects will incur no cost for their participation.  
15.2
Compensation for research-related injury
It is the policy of the institution to provide neither financial compensation nor free medical treatment 
for research-related injury. In the event of injury resulting from this research, medical treatment is 
available but will be provided at the usual charge.  Costs for the treatment of research-related injuries 
will be charged to subjects or their insurance carriers.
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16.0 Resources Available
16.1
Facilities and locations
For Part 1, the consent procedure will be conducted within the ALS Clinic at 30 Hope Drive on the 
Hershey Medical Center campus.  The clinic houses a room set up by the Penn State Hershey 
information technology department that is dedicated to ALS telemedicine.  This room will also be used 
as the site for the respiratory therapist to conduct the rPFT assessment.  This research room is in a 
private location and contains all the tools necessary for engaging in secure videoconferencing.
For Part 2, consent may be obtained in the ALS clinic or over the telemedicine interface.  The home of 
the patient will be the site of most of the study procedures.  When engaging in procedures via 
telehealth, a member of the study team will communicate with the participant from a private office or 
from a research room in the ALS clinic.  The study team will exclusively use the HIPAA-compliant HMC 
Telemedicine system by AmWell that is used for routine clinical care of ALS patients.  
16.2
Feasibility of recruiting the required number of subjects
We anticipate high interest in Part 1 due to the short time commitment and participation during a single 
clinical visit.  We anticipate no issues recruiting 40 individuals for this study.  The resource and timing 
limitations of Part 2 will make enrollment more challenging.  We expect to screen and consent 60 
participants, with the goal of having 40 participants meet the endpoint criteria.  We anticipate the 
participation of two respiratory therapists to aid with rPFT administration.
16.3
PI Time devoted to conducting the research
The PI has devoted 25% time to oversight of this project, involving discussion the goals, procedures, 
analysis, and data review, as well as input on clinical matters as requested by members of the study 
team. 
16.4
Availability of medical or psychological resources
If any medical or psychological resources are found to be needed during the course of the study, the 
participant will be directed to contact his/her Primary Care Provider or emergency care if warranted.
16.5
Process for informing Study Team
Before recruitment and any time a change is made to the protocol, the study team will meet to discuss 
changes in their role within the study, if applicable.
17.0 Other Approvals
17.1
Other Approvals from External Entities
N/A
17.2
Internal PSU Committee Approvals
Check all that apply:
  Anatomic Pathology – Hershey only – Research involves the collection of tissues or use of pathologic 
specimens. Upload a copy of HRP-902 - Human Tissue For Research Form on the “Supporting 
Documents” page in CATS IRB. This form is available in the CATS IRB Library.  
  Animal Care and Use – All campuses – Human research involves animals and humans or the use of 
human tissues in animals
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  Biosafety – All campuses – Research involves biohazardous materials (human biological specimens 
in a PSU research lab, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA 
or gene therapy).
  Clinical Laboratories – Hershey only – Collection, processing and/or storage of extra tubes of body 
fluid specimens for research purposes by the Clinical Laboratories; and/or use of body fluids that 
had been collected for clinical purposes, but are no longer needed for clinical use. Upload a copy of 
HRP-901 - Human Body Fluids for Research Form on the “Supporting Documents” page in CATS IRB. 
This form is available in the CATS IRB Library. 
  Clinical Research Center (CRC) Advisory Committee – All campuses – Research involves the use of 
CRC services in any way.
  Conflict of Interest Review – All campuses – Research has one or more of study team members 
indicated as having a financial interest.
  Radiation Safety – Hershey only – Research involves research-related radiation procedures. All 
research involving radiation procedures (standard of care and/or research-related) must upload a 
copy of HRP-903 - Radiation Review Form on the “Supporting Documents” page in CATS IRB. This 
form is available in the CATS IRB Library.
  IND/IDE Audit – All campuses – Research in which the PSU researcher holds the IND or IDE or 
intends to hold the IND or IDE.
  Scientific Review – Hershey only – All investigator-written research studies requiring review by the 
convened IRB must provide documentation of scientific review with the IRB submission. The 
scientific review requirement may be fulfilled by one of the following: (1) external peer-review 
process; (2) department/institute scientific review committee; or (3) scientific review by the Clinical 
Research Center Advisory committee.  NOTE: Review by the Penn State Hershey Cancer Institute 
Scientific Review Committee is required if the study involves cancer prevention studies or cancer 
patients, records and/or tissues. For more information about this requirement see the IRB website 
at: http://www.pennstatehershey.org/web/irb/home/resources/investigator 
18.0 Multi-Site Research
N/A
19.0 Adverse Event Reporting
19.1
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) 
experienced by a subject or other individual, which in the opinion of the investigator is determined to be 
(1) unexpected; and (2) probably related to the research procedures. Harms (adverse events) will be 
submitted to the IRB in accordance with the IRB policies and procedures.
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20.0 Study Monitoring, Auditing and Inspecting
20.1
Auditing and Inspecting
The investigator will permit study-related monitoring, audits, and inspections by the Penn State quality 
assurance program office(s), IRB, the sponsor, and government regulatory bodies, of all study related 
documents (e.g., source documents, regulatory documents, data collection instruments, study data 
etc.).  The investigator will ensure the capability for inspections of applicable study-related facilities 
(e.g., pharmacy, diagnostic laboratory, etc.).
The study will be monitored by the Clinical Trial Monitoring Team from the Department of Public Health 
Sciences at Penn State Hershey College of Medicine. The monitors will provide an independent review of 
the regulatory and subject records and the data collected to assure compliance with the protocol, GCP, 
and applicable federal regulations. The monitoring will occur at regular intervals after the enrollment of 
the first subject and the times will be predetermined by the monitoring plan developed by the Clinical 
Trial Monitoring Team.
21.0 Future Undetermined Research: Data and Specimen Banking
21.1
Data and/or specimens being stored
Clinical tests, surveys, and respiratory assessment results will be retained indefinitely for undefined 
future research.  All data will be labeled with the subject’s REDCap code. 
21.2
Location of storage
Digital data including respiratory test results and surveys will be retained on Dr. Geronimo’s 
Hersheymed.net drive in a password protected folder.  Clinical tests that are administered in paper form 
will be retained in the locked offices of the research team.
21.3
Duration of storage
Data will be stored for six years after study closure.
21.4
Access to data and/or specimens
The study team will have access to the data.  
21.5
Procedures to release data or specimens
Coded data, including surveys, clinical tests, and respiratory assessments will be made available to 
individuals performing research in ALS.  We will require a formal request from such researchers on 
Institutional letterhead.
21.6
Process for returning results
We will not return to study participants results derived from future undetermined research. 
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ALS - Maine Collaborative Teams Up with Massachusetts General Hospital for Better Care of Patients with Lou 
Gehrigs Disease, Dec 2010. Press Release.
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