Moderate Intensity Respiratory Muscle Training (RMT) in ALS
Phase: NA
Conditions: ALS
Sponsor: Duke University

Moderate intensity respiratory muscle training (RMT) in ALS 
NCT04224961 
 
Pro00103777 
PI: Harrison Jones, PhD 
Version date:  3.3.2021 
 
1.  Protocol Title:  
Moderate intensity respiratory muscle training (RMT) in ALS 
 
2.  Purpose of the Study:  
The purpose of this study is to develop treatments that enhance or preserve respiratory strength and 
provide meaningful clinical improvements for people with ALS and other neurodegenerative diseases 
with respiratory muscle involvement. Our central hypothesis is that moderate intensity RMT, 
individually modulated based on RPE, is necessary to induce meaningful changes in respiratory muscle 
strength and other outcomes in subjects with ALS. Our objectives are to: 
 
1) Determine the safety and feasibility of moderate intensity RMT in subjects with ALS targeting 
both the inspiratory and expiratory muscles using patient-reported ratings of perceived effort 
(RPE) to monitor and regulate intensity.   
2) Make preliminary estimates of the effects of moderate intensity RMT on respiratory muscle 
strength, cough and swallowing, and quality of life. 
 
We expect that moderate intensity RMT regulated with RPE (Foster et al., 2017) will be safe and well-
tolerated across subjects, though the magnitude of response, based on changes in respiratory muscle 
strength, is expected to vary based on baseline respiratory muscle strength. That is, based on effect size 
calculations, we expect subjects with normal inspiratory muscle strength to demonstrate large to very 
large increases in respiratory muscle strength, while subjects with mild to moderate inspiratory muscle 
weakness (40-70% of predicted) will demonstrate a more modest response. Culmination of these 
objectives will provide pilot data for submission of a competitive NIH grant application to further study 
RMT in ALS in a larger group of subjects.  
 
3.  Background & Significance:  
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the human motor system that 
results in progressive muscle weakness. Respiratory muscle weakness is present in more than 80% of 
patients at diagnosis, progresses as the disease advances, and is the primary cause of morbidity and 
mortality. Expiratory muscle weakness leads to diminished cough capacity (Park et al., 2010) and 
development of pneumonia, while inspiratory muscle weakness leads to hypoventilation and respiratory 
failure. Respiratory muscle strength is correlated with quality of life (QOL) and functional status 
(Bourke et al., 2001). There are no direct treatments for inspiratory and expiratory muscle weakness in 
ALS and such treatments are therefore an important unmet medical need.  
 
The estimated prevalence of ALS in the U.S. is 5 per 100,000 (Mehta et al., 2018). Most individuals 
with ALS die within 2-5 years after diagnosis due to respiratory failure and pneumonia associated with 
progressive respiratory muscle weakness (Corcia et al., 2008; Wolf et al., 2017). There is no cure for 
ALS and the lack of proven efficacious treatments is an ongoing challenge. Considering the morbidity 
and mortality associated with progressive respiratory muscle weakness, treatments that target inspiratory 
and expiratory muscle weakness in ALS remain an urgent medical need.  
 
Historically, patients with ALS have been counseled to avoid exercise and limit physical activity to 
preserve muscle strength and function, but this is now known to result in deconditioning and muscle 
atrophy that exacerbates the disease pathology (Clawson et al, 2017: Merico et al., 2018). Although 
concerns persist that high intensity exercise may exacerbate ALS disease progression (Lui & Byl, 2009), 

Moderate intensity respiratory muscle training (RMT) in ALS 
NCT04224961 
 
Pro00103777 
PI: Harrison Jones, PhD 
Version date:  3.3.2021 
 
recent data suggest that supervised moderate intensity resistance and/or endurance training programs in 
ALS are safe and well-tolerated (Clawson et al, 2017; Merico et al., 2018) and may enhance functional 
independence, muscle power, oxygen consumption, fatigue, and atrophy (Merico et al., 2018).   
 
Over the last decade, there has also been increased interest in applying resistance training to the 
respiratory muscles in ALS. Respiratory muscle training (RMT) is typically accomplished using hand-
held devices to provide resistance against inspiration (inspiratory muscle training [IMT]) or expiration 
(expiratory muscle training [EMT]). Previous data on the effects of RMT in ALS suggests that IMT and 
EMT are safe and well-tolerated by participants, though the effects on respiratory muscle strength and 
other outcome measures has been mixed (Cheah et al., 2009; Pinto et al., 2012; Plowman et al., 2016). 
However, previous efforts suffer many limitations which must be considered in future research. For 
example, prior investigations have used either IMT (Cheah et al., 2009; Pinto et al., 2012) or EMT in 
isolation (Plowman et al., 2016) instead of combining these approaches in a comprehensive RMT 
regimen that addresses both the inspiratory and expiratory muscles. Additionally, prior studies have 
prescribed relatively low intensity training regimens (Cheah et al., 2009; Pinto et al., 2012; Plowman et 
al., 2016). Furthermore, a methodology to monitor and modulate RMT intensity in ALS has not been 
developed. These are critical limitations as low intensity training may provide an insufficient dose of 
RMT, while high intensity RMT may be unsafe for ALS patients.   
 
Our laboratory has pioneered the use of moderate intensity RMT regimens to provide respiratory muscle 
resistance training and address progressive neuromuscular weakness (Jones et al, 2011, 2014, 2016). 
Counteracting respiratory muscle weakness with moderate intensity exercise offers a biologically 
plausible mechanism to target progressive inspiratory and expiratory muscle weakness in ALS. This 
research will be the first study of a comprehensive RMT program targeting both inspiratory muscle 
weakness with IMT and expiratory muscle weakness with EMT in individuals with ALS. We will also 
utilize a well-defined, moderate intensity RMT regimen and pioneer the use of patient-reported RPE to 
monitor and regulate intensity. We will use telehealth visits to collect measures of respiratory muscle 
strength (maximum inspiratory pressure [MIP], maximum expiratory pressure [MEP]) in order to 1) 
reduce the number of on-site visits required by participants and 2) improve our ability to collect repeated 
measures of our primary outcomes. We will continue to use the novel modifications, methods, and 
technologies we have developed to allow progressive, individualized, and calibrated RMT to be 
delivered across the range of human performance. These include our calibration methodology to ensure 
accurate, precise RMT pressure-threshold resistance (Jones et al., 2014, 2016) and the Inspiratory 
Adapter 150 (US Patent Pending) to allow use of expiratory-type devices for IMT (EMST 150; Aspire 
LLC) and expand the range of resistance. 
 
The results of this study will be used to refine our RMT in ALS treatment regimen, select appropriate 
outcome measures, and develop the statistical analysis plan for use in a future NIH grant application to 
further study RMT in ALS in a larger group of subjects.  
 
4.  Design & Procedures:  
Participants will be recruited from the Duke ALS Clinic or referred through CT.gov or outside hospitals. 
Twelve adults will participate in a single- subject A1-B-A2 study involving 4 visits to Duke over 24 
weeks (see Figure 1). The 6 week delayed start period represented by A1 will establish baseline status 
prior to initiation of RMT and A2 will determine detraining effects over 6 weeks of RMT withdrawal. 
Participants will complete four 3-week cycles of progressive RMT during the B phase. We will measure 

Moderate intensity respiratory muscle training (RMT) in ALS 
NCT04224961 
 
Pro00103777 
PI: Harrison Jones, PhD 
Version date:  3.3.2021 
 
MIP and MEP weekly. To reduce participant burden and enhance our ability to obtain repeated 
measures, we will have the ability to obtain measurements of MIP and MEP during web-based telehealth 
visits. 
 
Participants will complete a full assessment during the first study visit (M1), which may be performed in 
person or remotely via a web-based session, and receive training/instruction for obtaining MIP and MEP 
measurements at home with a portable, battery-powered digital pressure gauge manometer (MicroRPM 
Pressure Meter; Micro Direct). Prior to the pretest visit, participants who opt for remote visits will be 
mailed instructions for the home-based RMT regimen and the devices as well as a written treatment log. 
The pretest visit (M7) will include a full assessment after which RMT will commence. During the B 
phase, participants will complete 12-weeks of moderate intensity RMT, divided into four 3-week cycles, 
and participate in weekly web-based RMT therapy visits (M8-M18). Posttest assessment (M19) will 
occur immediately following completion of the 12-week RMT regimen. We will measure MIP and MEP 
during RMT withdrawal via web-based telehealth visits (M20-24). Following the fourth and final full 
assessment visit (M25), participants will return all equipment and will be offered the opportunity to 
initiate a clinical RMT regimen and receive follow-up care by Speech Pathology during future ALS 
Clinic visits.  
Note: If M1, M7, M19, and M25 are completed remotely, the Peak Cough Flow will not be able to be 
measured. 
 
Participants will be stratified into 2 groups based on baseline inspiratory muscle strength as determined 
by maximum inspiratory pressure (MIP): six participants with minimal to no respiratory weakness (i.e., 
MIP ≥ 70% predicted) and six participants with mild to moderate inspiratory weakness (i.e., MIP 40-
70% predicted). 
 
The primary outcomes are MIP and MEP. Secondary outcomes include peak cough flow (PCF) and sniff 
nasal inspiratory pressure (SNIP). Exploratory outcomes include the Amyotrophic Lateral Sclerosis 
Functional Rating Scale (ALSFRS), Eating Assessment Tool – 10 Item (EAT-10), 36-Item Short Form 
Survey (SF36), World Health Organization Quality of Life-BREF (WHOQOL-BREF), and 
Communicative Effectiveness Survey-Revised (CES-R). Outcomes will be collected as shown in Figure 

Moderate intensity respiratory muscle training (RMT) in ALS 
NCT04224961 
 
Pro00103777 
PI: Harrison Jones, PhD 
Version date:  3.3.2021 
 
1 following established guidelines (ATS/ERS 2002; Evans & Whitelaw 2009, Tzani 2014; Kaminska et 
al 2017; Cedarbaum et al 1999; Belafsky et al 2008; Ware & Sherbourne 1992; Donovan 2013). Clinical 
spirometry data will be extracted from the participant’s electronic medical record if available from a 
coinciding ALS Clinic visit that occurs +/- 5 days from the assessment visit.    
 
5.  Selection of Subjects: 
Inclusion criteria: 
• Age ≥ 18 years 
• Confirmed diagnosis of ALS 
• Ability to follow directions for study participation 
• Ability to successfully and independently complete RMT repetitions at a minimum pressure-
threshold target equal to 30% of MIP or MEP 
• Ability to complete telehealth visits using a smartphone or computer with video capabilities 
• Ability to complete a home-RMT regimen  
 
Exclusion criteria:  
• MIP < 40 cmH20 
• Presence of a tracheostomy  
• Use of non-invasive or invasive ventilation when awake  
• Participant or caregiver(s) inability to manipulate respiratory pressure meter, the RMT device, or 
calibration equipment for home training 
• Inability to complete RMT repetitions successfully  
• Concomitant neurologic or neurodegenerative conditions (e.g. stroke, dementia) or other serious 
conditions that would prevent meaningful study participation as determined at the discretion of 
the principal investigator  
• Inability to give legally effective consent 
• Inability to read and understand English 
 
6.  Subject Recruitment & Compensation: 
Participants will be recruited from the multidisciplinary Duke ALS Clinic, an ALS Association Certified 
Center that actively follows approximately 400 patients per year. Potential subjects will be identified by 
review of medical records by study staff. Subjects may also be referred through CT.gov or outside 
hospitals. Potentially eligible subjects will then be approached by the study coordinator, PI, or other 
member of the study team trained in conducting the informed consent process. This may be done via 
Mychart, email, letter or phone. For non-Duke patients, records will be requested from the outside 
hospital to confirm eligibility. Patient opt-out status within Maestro Care will be reviewed before 
potential subjects are approached or communicated with. An opportunity to participate in the study will 
be offered to all DUHS patients or referrals who meet the inclusion/exclusion criteria, regardless of 
demographic group. Patients will be compensated $25 upon completion of each visit at Duke for a total 
of $100.  
 
7.  Consent Process:  
The consent process will be conducted by the PI and study team designated to conduct the consent. The 
potential subject will have as much time as they need to decide if they would like to participate or not. 
The potential subject will be encouraged to take the consent home and discuss it with any family 
members if they wish. Once the study is explained, all questions have been answered, and the subject 

Moderate intensity respiratory muscle training (RMT) in ALS 
NCT04224961 
 
Pro00103777 
PI: Harrison Jones, PhD 
Version date:  3.3.2021 
 
agrees, consent will be obtained. Consent will take place via phone script with eConsent, which is 
available via REDCap. This functionality provides the ability to consent remote participants or 
participants in clinic via tablets or touchscreen device.  Participants will have the capability to sign 
electronically with a stylus, mouse, or finger. Once the consent form is submitted, participants will 
receive an email that includes a PDF attachment with a copy of the signed consent form. The PDF will 
be emailed to Health Information Management from REDCap for incorporation into Epic. 
To minimize the possibility of coercion or undue influence, potential participants will be given ample 
time to ask questions and review the consent form. In addition, it will be stressed that participation in 
this study does not alter the treatment course and that participation is completely voluntary. The 
potential participant will be provided with the name and contact information for the study coordinator 
and the PI and the Duke IRB in the event of questions or concerns after reviewing the consent.  
 
8.  Subject’s Capacity to Give Legally Effective Consent: 
Legally effective informed consent will be obtained for all subjects. “Legally effective” means that the 
subject 1) has sufficient information to make a decision, 2) understands the consequences of a decision, 
(3) is able to make a decision, and 4) is able to communicate a decision. If a potential subject is 
incapable of informed decision-making, consent from their legally authorized representative (LAR) will 
not be sought, as the cognitive-communication skills necessary for informed consent are also necessary 
for participation in the research. The study will include high functioning ALS patients who may not be 
able to physically sign the ICF due to disease related muscle weakness so we will include an LAR and 
witness signature line.  
 
9.  Study Interventions: 
During the 12-week intervention period, participants will complete a home-based RMT program and 
participate in weekly web-based RMT therapy sessions (M8-M18). RMT will be divided into four 3-
week cycles. Participants will begin RMT immediately after completing assessments during the pretest 
visit (M7; see Figure 1). During this visit, participants will demonstrate ability to complete RMT 
repetitions successfully, and will be provided with all the necessary training and equipment to complete 
home RMT for the next 12 weeks. 
 
Two commercially available pressure-threshold RMT devices that utilize a spring-loaded flange to 
provide resistance against inspiration and expiration independent of respiratory flow rate will be used to 
provide the necessary range of resistance. Each participant will use two RMT devices, one for IMT and 
one for EMT. Device selection will be based on the target pressure-threshold resistance (see Figure 2). 
Participants requiring pressure-threshold resistance between 40 and 150 cm H2O for expiratory training 
will use the EMST 150 device (Aspire, LLC). Expiratory resistance between 9 and 40 cm H2O will be 
provided by the Threshold IMT device (Philips Respironics), achieved by placing the mouthpiece on the 
opposite end of the device. The Threshold IMT device will be used to provide pressure-threshold 
resistance between 9 and 40 cm H2O for inspiratory training. The EMST 150 will also be used to 
provide pressure-threshold resistance between 41 and 150 cm H20 for inspiratory training, using the 
Inspiratory Adapter 150 (Aspire, LLC).  
 
Device 
Inspiratory Training Range 
Expiratory Training Range 
EMST 150 
41-150 cm H2O  
(with Inspiratory Adaptor 150) 
 
40-150 cm H2O 
Threshold IMT 
9-40 cm H2O 
9-40 cm H20 

Moderate intensity respiratory muscle training (RMT) in ALS 
NCT04224961 
 
Pro00103777 
PI: Harrison Jones, PhD 
Version date:  3.3.2021 
 
                Figure 2. Each participant will receive two RMT devices; device selection is dependent on target pressure- 
                threshold resistance.  
 
We will evaluate the feasibility of telehealth visits by conducting assessment of MIP/MEP, device 
calibration, and RMT via web-based video conferencing. Participants will perform inspiratory and 
expiratory repetitions at a calibrated, individualized pressure-threshold resistance based on measurement 
of MIP (for inspiratory training) and MEP (for expiratory training). A licensed speech-pathologist with 
expertise in RMT (the “RMT clinician”) will provide the intervention following a pre-determined 
algorithm and shape participant performance with instructions, cues, and demonstrations as necessary to 
facilitate success during each study visit. Every three weeks, a new RMT cycle will begin and the 
pressure-threshold target will be adjusted during the web-based visit based on each participant’s current 
MIP/MEP. Participants and/or caregivers will receive guidance to calibrate the RMT devices to the 
target pressure-threshold. Calibration will be accomplished by establishing a 3-way connection to a 
portable differential atmospheric pressure gauge/meter to ensure accuracy of dose delivered (Jones et al., 
2016). Intensity of RMT will be monitored and regulated visit based on RPE.  
 
During the initial RMT session (M7), all 
participants will initiate RMT at 50% of their 
MIP (for IMT) and MEP (for EMT). The 
pressure-threshold target will be systematically 
increased or decreased in 5% increments until 
moderate intensity is established. Safe, well-
tolerated moderate intensity RMT is defined as: 
1. RPE between 4-5 and <6 (Foster et al., 
1998; see Figure 3) 
2. Pain rating <4 on a standard 0-10 scale 
3. Accuracy >90% for the last 10 of 25 
repetitions in a set 
4. Behavioral observations indicate 
repetitions are well tolerated.  
 
Once the appropriate target pressure-threshold is 
established, participants will then complete 1 set each of 25 repetitions of IMT and EMT at this 
pressure-threshold to ensure safety and tolerance. Intensity will be adjusted as needed during the session 
based on the accuracy of repetitions, pain ratings, and behavioral observations to ensure that RMT is 
moderate in intensity and safe and well-tolerated (see Figure 4).  
 
Instructions for the home-based RMT program will be provided at the conclusion of each RMT therapy 
session. Participants will gradually increase RMT intensity during each 3-week cycle by increasing the 
number of repetitions performed. During the first week of each interval, participants will complete 1 set 
of 25 repetitions for each IMT and EMT 5 days per week (125 IMT and 125 EMT repetitions, 
cumulatively). During week 2, the number of RMT repetitions will increase to 2 sets of 25 for both IMT 
and EMT 5 days per week (250 IMT and 250 EMT repetitions, cumulatively). During week 3, 3 sets of 
25 repetitions for both IMT and EMT will be completed 5 days per week (375 IMT and 375 EMT 
repetitions, cumulatively). Overall, participants will be prescribed 6000 RMT repetitions (3000 IMT and 
3000 EMT) over the 12-week treatment phase of the study. 
 

Moderate intensity respiratory muscle training (RMT) in ALS 
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PI: Harrison Jones, PhD 
Version date:  3.3.2021 
 
In weeks 2 and 3 of each 3-week cycle, MIP and MEP will be measured and the RMT Clinician will 
observe the participant completing the appropriate number of repetitions for the week to ensure safety 
and tolerance. If the participant reports pain >3, RPE >5, accuracy is <90% for the last 10 of 25 
repetitions in a set, or if behavioral observations indicate RMT is poorly tolerated after increasing the 
number of repetitions, the pressure-threshold target will be systematically decreased in 5% increments 
until moderate intensity is re-established (see Figure 5). 
 
At the beginning of each of the remaining 3-week cycles (M10, M13, M16), the pressure-threshold 
target will be adjusted in a stepwise fashion with the goal of providing safe, progressive moderate 
intensity RMT as measured by RPE. The pressure-threshold target will be systematically increased or 
decreased in 5% increments as previously described until moderate intensity is established.  
 
The maximum training load will be 70% of MIP/MEP, whereas the minimum training load will be 30% 
of MIP/MEP. This is considered to be the minimum treatment intensity required to induce muscle 
hypertrophy and strength increases. If a participant is unable to complete RMT repetitions successfully 
(>90% accuracy for the last 10 of 25 repetitions in a set) and safely (RPE <6, pain<4) at 30% MIP/MEP, 
they will be withdrawn from the research by the PI.  
 
Participants will be asked to keep a paper log documenting the number of repetitions they complete each 
day as well as RPE and any pain they experience associated with home RMT.  
 
See Figure 4 and Figure 5 for a detailed treatment decision tree and sequential list of treatment 
activities for each study visit.  
 
10. Risk/Benefit Assessment: 
Research participation is expected to be safe and well-tolerated based on our prior research using 
moderate intensity RMT in late-onset Pompe disease (Jones et al, 2011, 2014, 2016) and the relevant 
research in the ALS literature (Cheah et al., 2009; Pinto et al., 2012; Plowman et al., 2016). Multiple 
elements of our study design have been included to ensure rigorous safety monitoring and minimize risk 
including:  
• Individualized, stepwise pressure-threshold resistance based on each subject’s respiratory muscle 
strength and RPE; 
• Weekly contact with the RMT clinician during the 12-week training period to foster adherence 
and assess for any negative side effects; 
• A predetermined algorithm for modulating RMT intensity to ensure participant safety; 
• Use of an experienced RMT clinician to conduct the RMT program with training and oversight 
by the PI; 
• Calibration of RMT devices to ensure precise and accurate pressure-threshold resistance. 
 
11. Costs to the Subject:  
There are no costs to subjects to participate in this study.  
 
12. Data Analysis & Statistical Considerations: 
Descriptive statistics will be provided for all outcomes. Primary outcome measures of MIP and MEP 
will be analyzed using visual analysis of raw data in graphical format using the method described by 
Land and Gast (2014). Magnitude of change for our primary outcome measures will be determined using 

Moderate intensity respiratory muscle training (RMT) in ALS 
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PI: Harrison Jones, PhD 
Version date:  3.3.2021 
 
Cohen’s measure of effect size (d) as defined by the first equation for single-subject d provided by Busk 
and Serlin (1992). Simply stated, d is obtained by subtracting the mean of the first assessment from the 
mean of the second assessment, divided by the standard deviation of the first assessment. Effect size 
calculations will be determined to compare results from baseline (M0-M5) to withdrawal (M19-M24) 
and pretest (M7) to posttest (M18). We will use conservative interpretation guidelines for effect size 
calculations in which d < 0.6 is negligible, d ≥ 0.6 modest, d ≥ 1.0 large, and d ≥ 2.0 very large.  
 
13. Data & Safety Monitoring:  
Data will maintained in REDCap and reviewed by the PI at regular intervals to ensure accurate and 
timely data collection. 
 
During the treatment phase of the study, the RMT clinician will collect safety and adverse event 
information from study participants each week during RMT therapy telehealth sessions. As described 
above, if accuracy is below 90% for the last 10 of 25 repetitions in a set, pain rating ≥ 4, perceived effort 
ratings ≥ 6, or if behavioral observations indicate inspiratory and/or expiratory repetitions are not well 
tolerated (regardless of pain or effort ratings), treatment intensity will be decreased by modifying 
pressure-threshold targets in 5% increments until RMT is well tolerated. The RMT clinician will contact 
the PI for further guidance in the event that these modifications to not result in well-tolerated repetitions. 
If subjects do not achieve the 90% accuracy criterion during the final 10 IMT/EMT repetitions in the 
session, the RMT clinician will determine if the trainer settings should remain unchanged or decrease for 
the subsequent home-based RMT. This determination will be based on the overall subject performance 
and behavioral observations as fatigue may be a factor impacting performance by the end of the session. 
 
14. Privacy, Data Storage & Confidentiality: 
Study records that identify subjects will be kept confidential as required by law. Federal Privacy 
Regulations provide safeguards for privacy, security, and authorized access. Except when required by 
law, subjects will not be identified by name, social security number, address, telephone number, or any 
other direct personal identifier in study records disclosed outside of Duke University Health System 
(DUHS). Subjects will be assigned and identified by a unique identification number at the time of 
enrollment. This number will be used to identify the subject throughout the study and will remain with 
the subject throughout the duration of the study.  
 
Study data including demographic and experimental data will be stored using REDCap. REDCap is a 
software tool that does not require client local software and can be accessed from anywhere on the Internet 
and is secured on a Duke Health Technology Services (DHTS) server. This database will be developed 
and maintenance performed with support of the School of Medicine (SOM) Duke Office of Clinical 
Research (DOCR). SOM’s DOCR has partnered with the School of Medicine (SOM) to implement 
REDCap (developed by Vanderbilt’s CTSA and currently used and supported by more than 1600 
consortium partners. REDCap provides: 1) a stream-lined process for rapidly building a database; 2) an 
intuitive interface for collecting data (with data validation and audit trail); 3) automated export procedures 
for seamless data downloads to common statistical packages (SAS, SPSS, etc.); 4) branching logic, file 
uploading, and calculated fields; and 5) a quick and easy protocol set-up.  
 
REDCap accounts are stored within the DTMI LDAP server hosted by the Duke Office of Information 
Technology (OIT). Authentication occurs via the OIT implementation of Kerberos. All connections to the 
system, both external and internal, occur over encrypted channels. Access to components of the system is 

Moderate intensity respiratory muscle training (RMT) in ALS 
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Version date:  3.3.2021 
 
role-based and can only be granted by administrators of the system. All collected information is stored on 
a database server hosted by Duke Health Technology Services (DHTS). The database server resides 
behind the DHTS internal firewall and access to the server is controlled via firewall rules. All collected 
data are backed up daily, both on the local server and by the DHTS enterprise backup system.  
Electronic files including the screening and enrollment log will be retained in a secure, study-specific 
folder on a secure network, accessible only to study personnel. Regulatory documents will be kept in a 
locked file in the office of the HNSCS research staff (Room 3576, White Zone), which is locked when 
not in use. Paper-based source documents will be kept in separate locked files in the office of Dr. 
Harrison Jones (Room 2504, Blue Zone), which is locked when not in use.  
 
Subject records may be reviewed for compliance with federal or state regulations, or institutional 
guidance. Reviewers may include representatives from the Food and Drug Administration, the Duke 
IRB, and the Duke Ethics and Compliance Office. If any of these groups review research records, they 
may also need to review the participant’s medical record.  
 
Potential risk of the loss of confidentiality cannot be eliminated. However, this risk is minimized by use 
of locked cabinets/containers in locked rooms for storage of physical data; the high level of electronic 
security for all Duke computer systems; the annual patient confidentiality training required by faculty, 
staff, students, and trainees at Duke University Health System/Duke University Hospital; and the human 
subjects research training required by all research personnel.   
 
The study results will be retained for at least 6 years after the study is completed. After that time, 
research information not already in the medical record will be destroyed or identifying subjects will be 
removed from such study results at DUHS. Any research information in the medical record will be kept 
indefinitely. While the information and data resulting from this study may be presented at scientific 
meetings or published in scientific journals, the identity of research subjects will not be revealed.  The 
results of the study will not be submitted later, or held for inspection by the FDA, for a future device 
application or marketing application. 
 
 

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Figure 4. Treatment flow chart/decision tree for RMT Cycle 1. Treatment will be individualized following a pre-determined algorithm to 
establish moderate intensity RMT that is safe and well-tolerated.  
 
RMT Cycle 1 
Week 1: 
Week 2: 
Week 3: 
Measure MIP and MEP 
Measure MIP and MEP 
Measure MIP and MEP 
Set initial pressure threshold to 50% of 
MIP/MEP 
Review RMT adherence  
and performance data from  
prior 3 weeks of home RMT 
Review RMT adherence  
and performance data from  
prior 3 weeks of home RMT 
Complete up to 5 trial RMT repetitions to 
establish moderate intensity with RPE = 4-5. 
Repeat as necessary. 
Home RMT 
accuracy >90% w/ 
pain <4 and RPE 4-
5: begin 
repetitions.  
 
 
Home RMT 
accuracy <90%, 
pain >4, or RPE >6: 
Subtract 5% from 
home RMT therapy 
target  
and begin training 
at this % of 
MIP/MEP 
Home RMT 
accuracy >90% w/ 
pain <4 and RPE 4-
5: begin 
repetitions.  
 
 
Home RMT 
accuracy <90%, 
pain >4, or RPE >6: 
Subtract 5% from 
home RMT therapy 
target  
and begin training 
at this % of 
MIP/MEP 
Complete 50 IMT and 50 EMT repetitions.  
Collect pain rating, RPE, and behavioral 
observations. Calculate overall % 
accuracy. 
Complete 75 IMT and 75 EMT repetitions.  
Collect pain rating, RPE, and behavioral 
observations. Calculate overall % 
accuracy. 
RPE 0-3:  
Increase 
pressure 
threshold 
target by 5%  
(Maximum = 
70% of 
MIP/MEP) 
and attempt 
5 additional 
trial RMT 
repetitions 
RPE 4-5:  
Appropriate 
pressure 
threshold 
identified 
 
RPE >6: 
Decrease 
pressure 
threshold 
target by 5%  
(Minimum = 
30% of 
MIP/MEP) 
RPE 4-5, pain <4, 
>90% accuracy 
over last 10 
repetitions, and 
behavioral 
observations 
indicate RMT is 
well tolerated:  
Pressure threshold 
target remains  
unchanged for 
home RMT 
RPE > 6, pain >4, 
<90% accuracy 
over last 10 
repetitions, or 
behavioral 
observations 
indicate RMT is not 
well tolerated: 
Pressure threshold 
target reduced by 
5%  
(Minimum = 30% of 
MIP/MEP) 
RPE 4-5, pain <4, 
>90% accuracy 
over last 10 
repetitions, and 
behavioral 
observations 
indicate RMT is 
well tolerated:  
Pressure threshold 
target remains  
unchanged for 
home RMT 
RPE > 6, pain >4, 
<90% accuracy 
over last 10 
repetitions, or 
behavioral 
observations 
indicate RMT is not 
well tolerated: 
Pressure threshold 
target reduced by 
5%  
(Minimum = 30% 
of MIP/MEP) 
Complete 25 IMT and 25 EMT repetitions.  
Collect pain rating, RPE, and behavioral 
observations. Calculate overall % accuracy. 
Provide instructions for home RMT:  
Week 2 = 2 sets 25 reps IMT and 
EMT/day, 5x/week (250 reps/week, each) 
Provide instructions for home RMT: 
Week 3 = 3 sets 25 reps IMT and 
EMT/day, 5x/week (375 reps/week, each) 
RPE 4-5, pain <4, 
>90% accuracy over 
last 10 repetitions, 
and behavioral 
observations 
indicate RMT is well 
tolerated:  
Pressure threshold 
target remains  
unchanged for home 
RMT 
RPE > 6, pain >4, 
<90% accuracy over 
last 10 repetitions, 
or behavioral 
observations 
indicate RMT is not 
well tolerated: 
Pressure threshold 
target reduced by 
5%  
(Minimum = 30% of 
MIP/MEP) 
 
 
Provide instructions for home RMT: 
Week 1 = 1 set 25 reps IMT and EMT/day, 
5x/week (125 reps/week, each) 
 
 

Moderate intensity respiratory muscle training (RMT) in ALS 
NCT04224961 
 
Pro00103777 
PI: Harrison Jones, PhD 
Version date:  3.3.2021 
 
Figure 5. Treatment flow chart/decision tree for RMT Cycles 2-4. Treatment will be individualized following a pre-determined algorithm 
to provide progressive, moderate intensity RMT that is safe and well-tolerated. 
RMT Cycles 2-4: 
Week 1: 
Week 2: 
Week 3: 
Measure MIP and MEP 
Measure MIP and MEP 
Measure MIP and MEP 
Review RMT adherence  
and performance data from  
prior 3 weeks of home RMT 
Review RMT adherence  
and performance data from  
prior 3 weeks of home RMT 
Review RMT adherence  
and performance data from  
prior 3 weeks of home RMT 
Home RMT accuracy 
>90% w/ pain <4 and 
RPE 4-5: Begin RMT 
therapy session at 
50% of today’s 
MIP/MEP. 
Subtract 5% from 
home RMT therapy 
target  
and begin training 
at this % of 
MIP/MEP 
Complete up to 5 trial RMT repetitions to 
establish moderate intensity with RPE = 4-5. 
Repeat as necessary. 
Home RMT 
accuracy >90% w/ 
pain <4 and RPE 4-
5: begin 
repetitions.  
 
 
Home RMT 
accuracy <90%, 
pain >4, or RPE >6: 
Subtract 5% from 
home RMT therapy 
target  
and begin training 
at this % of 
MIP/MEP 
Home RMT 
accuracy >90% w/ 
pain <4 and RPE 4-
5: begin 
repetitions.  
 
 
Home RMT 
accuracy <90%, 
pain >4, or RPE >6: 
Subtract 5% from 
home RMT therapy 
target  
and begin training 
at this % of 
MIP/MEP 
Complete 50 IMT and 50 EMT repetitions.  
Collect pain rating, RPE, and behavioral 
observations. Calculate overall % 
accuracy. 
Complete 75 IMT and 75 EMT repetitions.  
Collect pain rating, RPE, and behavioral 
observations. Calculate overall % 
accuracy. 
RPE 0-3:  
Increase 
pressure 
threshold 
target by 5%  
(Maximum = 
70% of 
MIP/MEP) 
and attempt 
5 additional 
trial RMT 
repetitions 
RPE 4-5: 
Appropriate 
pressure 
threshold 
identified 
 
RPE >6: 
Decrease 
pressure 
threshold 
target by 5%  
(Minimum = 
30% of 
MIP/MEP) 
RPE 4-5, pain <4, 
>90% accuracy 
over last 10 
repetitions, and 
behavioral 
observations 
indicate RMT is 
well tolerated:  
Pressure threshold 
target remains  
unchanged for 
home RMT 
RPE > 6, pain >4, 
<90% accuracy 
over last 10 
repetitions, or 
behavioral 
observations 
indicate RMT is not 
well tolerated: 
Pressure threshold 
target reduced by 
5%  
(Minimum = 30% of 
MIP/MEP) 
RPE 4-5, pain <4, 
>90% accuracy 
over last 10 
repetitions, and 
behavioral 
observations 
indicate RMT is 
well tolerated:  
Pressure threshold 
target remains  
unchanged for 
home RMT 
RPE > 6, pain >4, 
<90% accuracy 
over last 10 
repetitions, or 
behavioral 
observations 
indicate RMT is not 
well tolerated: 
Pressure threshold 
target reduced by 
5%  
(Minimum = 30% 
of MIP/MEP) 
Complete 25 IMT and 25 EMT repetitions.  
Collect pain rating, RPE, and behavioral 
observations. Calculate overall % accuracy. 
Provide instructions for home RMT:  
Week 2 = 2 sets 25 reps IMT and 
EMT/day, 5x/week (250 reps/week, each) 
Provide instructions for home RMT: 
Week 3 = 3 sets 25 reps IMT and 
EMT/day, 5x/week (375 reps/week, each) 
RPE 4-5, pain <4, 
>90% accuracy over 
last 10 repetitions, 
and behavioral 
observations 
indicate RMT is well 
tolerated:  
Pressure threshold 
target remains  
unchanged for home 
RMT 
RPE > 6, pain >4, 
<90% accuracy over 
last 10 repetitions, 
or behavioral 
observations 
indicate RMT is not 
well tolerated: 
Pressure threshold 
target reduced by 
5%  
(Minimum = 30% of 
MIP/MEP) 
Provide instructions for home RMT: 
Week 1 = 1 set 25 reps IMT and EMT/day, 
5x/week (125 reps/week, each) 

Moderate intensity respiratory muscle training (RMT) in ALS 
NCT04224961 
 
Pro00103777 
PI: Harrison Jones, PhD 
Version date:  3.3.2021 
 
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Moderate intensity respiratory muscle training (RMT) in ALS 
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Pro00103777 
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Version date:  3.3.2021 
 
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