Mechanical Insufflation in the Philadelphia Amyotrophic Lateral Sclerosis Cohort (MI-PALS) Study
Phase: NA
Conditions: Amyotrophic Lateral Sclerosis, Chronic Respiratory Failure, Airway Clearance Impairment, Neuromuscular Diseases
Sponsor: University of Pennsylvania

 
 
 
 
Protocol # 854981 - MI-PALS 
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Protocol Template V3.0 (09Nov2020) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mechanical Insufflation in the 
Philadelphia Amyotrophic 
Lateral Sclerosis Cohort (MI-
PALS) Study Protocol

 
 
Protocol # 854981- MI-PALS 
 
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Confidential and Proprietary Information of Jason Ackrivo, MD, MSCE 
 
CLINICAL RESEARCH PROTOCOL 
INVESTIGATIONAL 
PRODUCT(S): 
 
 
Mechanical insufflation (MI) is a chest physiotherapy 
exercise that will be performed using a type of 
mechanical insufflator-exsufflator (MI-E) (also 
known as a cough assist device) known as the 
BiWaze Cough device (Figure 1). This device is 
manufactured by ABM Respiratory Care and is 
designed for use on patients unable to cough or clear 
secretions effectively due to reduced peak cough 
expiratory flow, resulting from disease such as 
neuromuscular deficits. The device connects to a tube 
that can interface with a patient using either a 
facemask, mouthpiece, or an adapter to a patient's 
endotracheal tube or tracheostomy tube. It is FDA 
approved for use in the home on adult patients and 
pediatric patients 3 years old and up. 
 
 
 
 
 
 
 
 
 
 
 
Mechanical insufflation is a chest physiotherapy exercise 
that passively inflates the chest with positive pressure that 
is delivered in coordination with the patient’s own 
inspiratory timing until maximal inflation capacity (MIC), 
determined by the patient or maximal chest rise on visual 
inspection. At MIC, the patient passively exhales, which 
completes one “cycle”. Prior literature has used a “dose” 
of 5 sets of 5 cycles once or twice daily.1–4 The maneuver 

 
 
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Confidential and Proprietary Information of Jason Ackrivo, MD, MSCE 
 
is usually performed with assistance of a caregiver to hold 
the mask or mouthpiece in place. 
STUDY 
NUMBER(S): 
IRB Number 
854981 
Other Protocol 
Identifiers  
N/A 
PROTOCOL(S) TITLE: 
Mechanical Insufflation in the Philadelphia ALS 
Cohort (MI-PALS) Study 
IND/IDE/CTA NUMBER: 
 
N/A 
REGULATORY SPONSOR: 
Jason Ackrivo, MD, MSCE 
FUNDING SPONSOR(S): 
National Institutes of Health 
National Heart, Lung, and Blood Institute 
MEDICAL DIRECTOR 
Jason Ackrivo, MD, MSCE 
ORIGINAL PROTOCOL DATE: 
To be determined 
VERSION NUMBER: 
v1.1 
VERSION DATE: 
09.10.2025 
 
 

 
 
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Confidential and Proprietary Information of Jason Ackrivo, MD, MSCE 
 
1 
Study Summary ........................................................................................................ 10 
1.1 
Synopsis ................................................................................................................ 10 
1.2 
Key Roles and Study Governance ..................................................................... 13 
1.3 
Schema ................................................................................................................. 14 
2 
introduction and rationale ...................................................................................... 15 
2.1 
Study Rationale ................................................................................................... 15 
2.2 
Background .......................................................................................................... 15 
2.2.1 
Pharmacokinetics, Pharmacodynamics and Toxicology ........................... 16 
2.2.2 
Assessment for Potential Study Products Drug-Drug, Drug-Device, 
Device-Device Interactions ........................................................................... 16 
2.2.3 
Clinical Adverse Event Profile ..................................................................... 16 
2.2.4 
Dosing Rationale ............................................................................................ 16 
Risk/Benefit Assessment ................................................................................................. 17 
2.2.5 
Known Potential Risks .................................................................................. 17 
2.2.6 
Known Potential Benefits ............................................................................. 17 
2.2.7 
Assessment of Potential Risks and Benefits ................................................ 18 
3 
Study Objectives and Endpoints ............................................................................. 20 
4 
Study Plan ................................................................................................................. 25 
4.1 
Study Design ........................................................................................................ 25 
4.2 
Scientific Rationale for Study Design ................................................................ 25 
4.3 
Justification for Dose .......................................................................................... 25 
4.4 
End of Study Definition ...................................................................................... 26 
5 
Study Population ...................................................................................................... 27 
5.1 
Inclusion Criteria ................................................................................................ 27 
5.2 
Exclusion Criteria ............................................................................................... 27 
5.3 
Lifestyle Considerations ..................................................................................... 28 
5.4 
Screen Failures .................................................................................................... 28 
5.5 
Strategies for Recruitment and Retention ........................................................ 28 
6 
Study Intervention ................................................................................................... 30 
6.1 
Study Intervention(s) Administration ............................................................... 30 
6.1.1 
Study Intervention Description .................................................................... 30 
6.1.2 
Dosing and Administration .......................................................................... 32 
6.1.3 
Instructions for initial set-up and determining optimum pressure, 
timing, and flow settings: .............................................................................. 33 
6.2 
Preparation/Handling/Storage/Accountability ................................................. 35 
6.2.1 
Acquisition and accountability ..................................................................... 35 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................ 35 
6.2.3 
Product Storage and Stability ...................................................................... 35 
6.2.4 
Preparation .................................................................................................... 36 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................. 36 
6.4 
Study Intervention Compliance ......................................................................... 36 
 

 
 
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6.5 
Concomitant Therapy ......................................................................................... 37 
6.5.1 
Rescue Medicine ............................................................................................ 37 
7 
Study Intervention Discontinuation and Participant 
Discontinuation/Withdrawal ................................................................................... 38 
7.1 
Discontinuation of Study Intervention .............................................................. 38 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................... 38 
7.3 
Lost To Follow-Up ............................................................................................... 39 
8 
Study Assessment and Procedures ......................................................................... 40 
8.1 
Efficacy Assessments ........................................................................................... 40 
8.1.1 
Peak cough flow (PCF) ................................................................................. 40 
8.1.2 
Forced vital capacity (FVC) ......................................................................... 41 
8.1.3 
Maximal inspiratory pressure (MIP) .......................................................... 41 
8.1.4 
Maximal expiratory pressure (MEP) .......................................................... 41 
8.1.5 
Maximum insufflation capacity (MIC) ....................................................... 41 
8.1.6 
MIC-assisted Peak Cough Flow ................................................................... 41 
8.1.7 
MIC-FVC difference ..................................................................................... 42 
8.1.8 
Transcutaneous carbon dioxide (TCO2) and oxygen saturation 
(SpO2) ............................................................................................................. 42 
8.1.9 
Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised 
(ALSFRS-R) dyspnea and orthopnea scores .............................................. 42 
8.1.10 
Global rate of change score for peak cough flow ....................................... 42 
8.1.11 
Start date of non-invasive ventilation (NIV) ............................................... 43 
8.1.12 
Tracheostomy-free survival time and death date ....................................... 43 
8.1.13 
ARC Connect data collection ....................................................................... 43 
8.2 
Safety and Other Assessments ........................................................................... 43 
8.2.1 
Consent ........................................................................................................... 43 
8.2.2 
Institutional Review Board process ............................................................. 43 
8.2.3 
Screening and enrollment ............................................................................. 43 
8.2.4 
Medical history .............................................................................................. 44 
8.2.5 
Physical exam ................................................................................................ 44 
8.2.6 
Vital signs ....................................................................................................... 44 
8.2.7 
Study assessments .......................................................................................... 44 
8.2.8 
Education of study intervention ................................................................... 44 
8.2.9 
Assessment of study intervention adherence .............................................. 44 
8.2.10 
Assessment of adverse events ....................................................................... 45 
8.3 
Adverse Events and Serious Adverse Events .................................................... 45 
8.3.1 
Definition of Adverse Events (AE) ............................................................... 45 
8.3.2 
Definition of Serious Adverse Events (SAE) ............................................... 45 
8.3.3 
Unanticipated Adverse Device Effect (UADE) ........................................... 46 
8.3.4 
Classification of an Adverse Event .............................................................. 46 
8.3.5 
Time Period and Frequency for Event Assessment and Follow-Up ......... 47 

 
 
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8.3.6 
Adverse Event Reporting ............................................................................. 49 
8.3.7 
Serious Adverse Event Reporting ................................................................ 51 
8.3.8 
Reporting Events to Participants ................................................................. 51 
8.3.9 
Events of Special Interest ............................................................................. 51 
8.3.10 
Reporting of Pregnancy ................................................................................ 52 
8.4 
Unanticipated Problems ..................................................................................... 52 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................ 52 
8.4.2 
Unanticipated Problem Reporting ............................................................... 52 
8.4.3 
Reporting Unanticipated Problems To Participants ................................. 53 
8.5 
Device Reporting ................................................................................................. 53 
9 
Statistical Considerations ........................................................................................ 54 
9.1 
Statistical Hypotheses ......................................................................................... 54 
9.2 
Sample Size Determination ................................................................................ 54 
9.3 
Populations for Analyses .................................................................................... 55 
9.4 
Statistical Analyses .............................................................................................. 56 
9.4.1 
General Approach ......................................................................................... 56 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................ 56 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................... 57 
9.4.4 
Safety Analyses .............................................................................................. 58 
9.4.5 
Baseline Descriptive Statistics ...................................................................... 58 
9.4.6 
Planned Interim Analyses ............................................................................. 59 
9.4.7 
Sub-Group Analyses ..................................................................................... 59 
9.4.8 
Exploratory Analyses .................................................................................... 59 
10 Supporting Documentation and Operational Considerations ............................. 59 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ............................. 59 
10.1.1 
Informed Consent Process ............................................................................ 59 
10.1.2 
Study Discontinuation and Closure ............................................................. 61 
10.1.3 
Confidentiality and Privacy ......................................................................... 62 
10.1.4 
Future Use of Stored Specimens and Data ................................................. 63 
10.1.5 
Safety Oversight ............................................................................................ 63 
10.1.6 
Clinical Monitoring ....................................................................................... 64 
10.1.7 
Quality Assurance and Quality Control ..................................................... 64 
10.1.8 
Data Handling and Record Keeping ........................................................... 65 
10.1.9 
Protocol Deviations ....................................................................................... 66 
10.1.10 
Publication and Data Sharing Policy ........................................................... 66 
10.1.11 
Conflict of Interest Policy ............................................................................. 67 
10.2 
Additional Considerations .................................................................................. 67 
10.3 
Protocol Amendment History ............................................................................ 67 
11 References ................................................................................................................. 68 
12 APPENDIX ............................................................................................................... 71 
12.1 
Schedule of Activities (SoA) ............................................................................... 71 

 
 
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PRINCIPAL INVESTIGATOR SIGNATURE 
 
STUDY 
SPONSOR: 
Jason Ackrivo, MD, MSCE 
Assistant Professor of Medicine 
Pulmonary, Allergy, and Critical Care Division 
Perelman School of Medicine at the University of Pennsylvania 
STUDY TITLE: 
Mechanical Insufflation in the Philadelphia Amyotrophic Lateral Sclerosis 
Cohort (MI-PALS) Study 
STUDY ID 
PROTOCOL 
VERSION 
IRB protocol # 854981 
v1.0 
I have read the referenced protocol. I agree to conduct the study in accordance to this protocol, in 
compliance with the Declaration of Helsinki, Good Clinical Practices (GCP), and all applicable 
regulatory requirements and guidelines. 
Principal 
Investigator Name  
Jason Ackrivo, MD, MSCE 
 
Signature 
 
Affiliation: 
University of Pennsylvania 
 
Date 
 
 
 
 
 
 
 

 
 
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Abbreviations 
AE 
Adverse Event 
ALS 
Amyotrophic Lateral Sclerosis 
ALSFRS-R 
Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised 
ALSSQOL-SF 
Amyotrophic Lateral Sclerosis specific quality of life questionnaire – short form 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
MP 
Monitoring Plan 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DSMB 
Data Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
DRE 
Disease-Related Event 
EMR 
Electronic Medical Record 
FDA 
Food and Drug Administration 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act  
ICH 
International Conference on Harmonization  
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
MI 
Mechanical insufflation 
MIC 
Maximal insufflation capacity 
MI-E 
mechanical insufflation-exsufflation 
MIP 
Maximal Inspiratory Pressure 
MOP 
Manual of Procedures 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIV 
Non-invasive ventilation 
OHRP 
Office for Human Research Protections 
PANAS 
Positive and Negative Affect Schedule 

 
 
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PCF 
Peak Cough Flow 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
DSMC 
Data Safety Monitoring Committee 
SoA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
SpO2 
Pulse oximetry oxygen saturation 
TCO2 
Transcutaneous partial pressure of carbon dioxide 
UADE 
Unanticipated Adverse Device Effect 
UP 
Unanticipated Problem 
US 
United States 
 
 
 

 
 
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1 STUDY SUMMARY 
1.1 
Synopsis 
Title:  
Mechanical Insufflation in the Philadelphia ALS Cohort (MI-PALS) 
Study 
Short Title: 
MI-PALS 
Study 
Description:  
We will study how performance of mechanical insufflation (MI) using a 
mechanical insufflator-exsufflator (MI-E) affects respiratory mechanics in early 
ALS. This will be a single-center, single-arm feasibility pilot study of MI in 20 
patients with ALS at Penn.  
 
Based on prior data,5–12 we hypothesize that 6-months of MI will be associated 
with a reduced decline in peak cough flow (PCF) compared to matched controls 
who do not use MI. 
 
We will perform MI using a device designed for mechanical insufflation-
exsufflation (MI-E) known as the BiWaze Cough system. Briefly, BiWaze 
Cough is a secretion clearance device that can sit on a bedside table. It is 
connected to corrugated tubing and mouthpiece (or anesthesia mask). The device 
will have preset pressure and timing settings. An assistant (or research subject) 
will operate the device via the touchscreen for 5 sets of 5 insufflations twice 
daily.  
Objectives:  
 
Supportive Care: MI will be evaluated for maximizing comfort, minimizing side 
effects, or mitigating against a decline in the participant's health or function. 
 
Primary 
Endpoint:  
 
Change in peak cough flow as measured by peak flow meter over a 6-month 
period. 
 
Secondary 
Endpoints: 
Forced vital capacity 
Maximum insufflation capacity 

 
 
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Maximum insufflation capacity minus vital capacity 
Maximum insufflation capacity assisted peak cough flow 
Maximal inspiratory pressure 
Maximal expiratory pressure 
ALS Functional Rating Scale – Revised (ALSFRS-R) total score 
ALSFRS-R dyspnea score 
ALSFRS-R orthopnea score 
Transcutaneous carbon dioxide level (daytime) 
Pulse oximetry (daytime) 
Global rate of change score for peak cough flow 
 
Tertiary 
Endpoints: 
 
Time to start of non-invasive ventilation 
Tracheostomy-free survival time 
 
Study 
Population: 
 
Adults (18+ years of age) diagnosed with amyotrophic lateral sclerosis 
who are seen at the Penn Comprehensive ALS Clinic at the University of 
Pennsylvania. We will target individuals with ALS who have an able and 
willing caregiver for assistance with MI. 
Phase: 
Post market 
Description of 
Sites/Facilities  
Penn Comprehensive ALS Center 
Opened in 1999, this outpatient specialized Neurology center has been 
designed to provide comprehensive, multidisciplinary care for people 
with ALS and their families. This clinic has over 500 total patient visits 
annually. Lead by Director, Dr. Lauren Elman, MD, the multidisciplinary 
care in this clinic includes Neurology, Pulmonology, nursing, nurse 

 
 
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practitioner, dietary, physical and occupational therapy, respiratory 
therapy, speech and language pathology, and genetic counseling. In 
addition, this clinic also participates in several clinical research studies, 
including multiple Phase 2 and 3 clinical trials. They have research staff, 
including site-PIs, a research coordinator, and medical personnel formally 
trained in clinical trial data collection. The clinic also contains a modern 
clinical-research grade spirometer, peak flow meter for peak cough flow, 
and a transcutaneous carbon dioxide monitor.  
 
Enrolling Sites: 
Penn Comprehensive ALS Center at the University of Pennsylvania. 
The site is located at 330 S. 9th Street, 3rd Floor, Philadelphia, PA, 19107 
Description of 
Study 
Intervention: 
We will perform mechanical insufflation (MI) using a type of mechanical 
insufflator-exsufflator (also known as a cough assist device) known as the 
BiWaze Cough device (Figure 1). This device manufactured by ABM 
Respiratory Care and is designed for use on patients unable to cough or 
clear secretions effectively due to reduced peak cough expiratory flow, 
resulting from disease such as neuromuscular deficits. The device 
connects to a tube that can interface with a patient using either a 
facemask, mouthpiece, or an adapter to a patient's endotracheal tube or 
tracheostomy tube. It is FDA approved for use in the home on adult 
patients and pediatric patients 3 years old and up. 
 
 
 
 
 
 
 
 
 
 
 
MI is a chest physiotherapy exercise that passively inflates the chest using 
positive pressure breaths delivered in coordination with the patient’s own 
inspiratory timing until maximal inflation capacity (MIC), determined by the 
patient or maximal chest rise on visual inspection. At MIC, the patient passively 
Figure 1. BiWaze Cough device 

 
 
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Confidential and Proprietary Information of Jason Ackrivo, MD, MSCE 
 
exhales, which completes one “cycle”. Prior literature has used a “dose” of 5 
sets of 5 cycles once or twice on prior data,5–12 The maneuver is usually 
performed with assistance of a caregiver. 
Study Duration: 
18 months 
Participant 
Duration: 
6 months 
 
 
 
 
 
1.2 
Key Roles and Study Governance 
Sponsor 
Medical Director 
Jason Ackrivo, MD, MSCE 
Assistant Professor of Medicine 
Pulmonary, Allergy, and Critical Care Division 
Assistant Professor of Neurology 
Hospital of the University of Pennsylvania 
 
Jason Ackrivo, MD, MSCE 
Assistant Professor of Medicine 
Pulmonary, Allergy, and Critical Care Division 
Assistant Professor of Neurology 
Hospital of the University of Pennsylvania 
 
Perelman School of Medicine at the University of 
Pennsylvania 
Perelman School of Medicine at the University of 
Pennsylvania 
3400 Spruce Street 
826 W. Gates Building 
Hospital of the University of Pennsylvania 
Philadelphia, PA 19104 
3400 Spruce Street 
826 W. Gates Building 
Hospital of the University of Pennsylvania 
Philadelphia, PA 19104 
215-662-3202 
215-662-3202 
Jason.ackrivo@pennmedicine.upenn.edu 
Jason.ackrivo@pennmedicine.upenn.edu 
 
 

 
 
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1.3 
Schema 
Prior to  
Enrollment  
Day (-7 to -1) 
 
 
 
 
Visit 1 
Day 1  
 
 
 
Visit 2 
Day 60  
(±14 days) 
 
 
 
Visit 3 
Day 120 
(±14 days) 
 
 
 
Final Visit 4 
Day 180 
(±14 days) 
 
 
 
Total N=20:  Obtain informed consent. Screen potential participants by 
inclusion and exclusion criteria; obtain history, document. 
Follow-up assessments of study endpoints and safety 
Perform assessments as highlighted in Appendix Section 12.1 Schedule of 
Activities 
Perform baseline assessments as highlighted in Appendix Section 12.1 
Schedule of Activities 
MI teaching and technique review 
Final Assessments 
refer to Appendix Section 
12.1, Schedule of Activities 
Arm 1 
20 participants 
Follow-up assessments of study endpoints and safety 
Perform assessments as highlighted in Appendix Section 12.1 Schedule of 
Activities 

 
 
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2 INTRODUCTION AND RATIONALE 
2.1 
Study Rationale 
Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease that commonly leads to respiratory 
failure related to weakened breathing and coughing. Current United States guidelines for respiratory care 
for ALS do not recommend any respiratory interventions until the patient meets specific thresholds such 
as FVC <50% predicted normal, MIP< -60 cmH2O, or nocturnal oxygen saturation <88% for ≥5 
minutes.13 ALS has a heterogenous presentation and rate of progression, and thus the window between 
diagnosis and meeting criteria for respiratory interventions could span months or even years during which 
breathing and coughing are weakening. An early respiratory intervention during this “waiting period”, 
when a person can still have weakened breathing and coughing, may offer an opportunity to slow 
progression of respiratory muscle weakness, strengthen coughing, and thus improve clinical outcomes.  
Most patients with ALS develop some respiratory muscle weakness, including weakened cough, prior 
to meeting the aforementioned guideline recommended thresholds. A device that can assist with 
weakened cough includes a mechanical insufflator-exsufflator (MI-E). A MI-E device can provide 
mechanical insufflation (MI), which helps expand the chest wall through the use of positive pressure 
through a mouthpiece or mask. The increased volume in the chest helps provide increased elastic recoil, 
thus strengthening cough. Prior studies have described the use of MI-E to provide mechanical insufflation 
in neuromuscular diseases.12,14 It remains unclear how early use of MI-E prior to guideline 
recommendations may help augment airway clearance and cough in ALS. Prior to performing a 
randomized trial, a feasibility study is necessary to estimate endpoint effect sizes, subject adherence, and 
adverse events. 
2.2 
Background 
As ALS causes progressive respiratory muscle weakness, hypoventilation, atelectasis, and chest wall 
restriction occur. Decreased chest wall movement creates contractures of sternocostal and costovertebral 
joints, progressively worsening chest wall restriction. Chest wall contracture plus weakening of the 
muscles contributes to weakened cough and airway clearance in ALS, which often can occur well before 
guidelines recommend instituting respiratory therapies.  
A major international expert panel for methods of airway clearance for neuromuscular disorders 
published a state-of-the-art review in 2018.12 Within this review, they highlight that use of mechanical 
insufflation (MI) via a MI-E device can provide assisted inspiration to achieve insufflation capacity. A 
MI-E device is an airway clearance device which sits on a flat surface and is connected to corrugated 
tubing attached to a mouthpiece or mask (as per patient preference or for those with bulbar 
weakness)(Figure 1). MI will inflate the chest via mask or mouthpiece by using positive pressure in 
coordination with the patient’s inspiratory timing until maximal inflation capacity (MIC), determined by 
the patient or maximal chest rise on visual inspection. At MIC, the patient removes the mask/mouthpiece 
and passively exhales, which completes one “cycle”. Prior literature on insufflation of the chest has used a 
“dose” of 5 sets of 5 cycles once or twice daily.5–11  
The maneuver is usually performed with assistance of a caregiver. This insufflation is believed to 
increase length of respiratory muscles, reduce chest wall restriction, and leverage the elastic recoil of the 
chest wall to increase cough peak flow and thus airway clearance. Multiple prior studies in neuromuscular 
disease (including ALS) has shown an improvement in cough efficacy, measured as peak cough flow, 
after using a MI-E device.5–11  

 
 
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This proposal aims to perform MI using a MI-E device. Contrary to respiratory muscle exercises that 
require active muscle contraction, MI is a passive maneuver that does not depend on strength and is thus 
ideal for ALS. MI may recruit atelectatic alveoli, improve chest wall range of motion, and slow decline of 
chest wall elasticity by preventing chest wall contractures. A critical knowledge gap includes whether 
several months of consistent MI use can improve respiratory outcomes in ALS. If proven effective, MI 
could serve as an early respiratory intervention which may delay respiratory decline, strengthen airway 
clearance ability, improve quality of life, and potentially prolong survival in ALS. 
 
Given the paucity of data on MI in ALS, we propose a single arm feasibility trial of the use of MI in 
individuals with early-stage ALS who are not yet on alternative respiratory therapy such as non-invasive 
ventilation. Our results from this trial will inform our next study enrolling high-risk patients into a RCT 
investigating early MI or NIV with the goal of improving quality life, clinical outcomes, and survival in 
ALS. 
2.2.1 
Pharmacokinetics, Pharmacodynamics and Toxicology 
Not applicable. 
2.2.2 
Assessment for Potential Study Products Drug-Drug, Drug-Device, 
Device-Device Interactions 
All eligible participants will be devoid of respiratory therapies at enrollment. However, it is possible 
that during the 6-months of follow-up the subject may begin alternative respiratory therapies such as non-
invasive ventilation (NIV) or require therapy assistance with cough strength MI-E. NIV would be used at 
separate time periods of the day and thus would not be used at the same time as the MI exercise. A cough 
that requires MI-E therapy to loosen secretions will be seen as an additional, augmented therapy in 
addition to the MI exercise described in this proposal. It is certainly possible that use of NIV or MI-E may 
attenuate the effects of MI alone; however, this has not borne out by the current literature.  
2.2.3 
Clinical Adverse Event Profile 
Side-effects and adverse events, as assessed by participant self-report. 
Potential side-effects associated with taking repeated deep breaths include discomfort or musculoskeletal 
soreness of the chest well, and light-headedness and/or transient fall in blood pressure.  
Although extremely rare, a pneumothorax can occur at very high inspiratory pressures and would 
constitute a serious adverse event. 
2.2.4 
Dosing Rationale 
The optimum “dose” of repetitions and sets to perform the MI maneuver is currently unknown. We 
will follow an MI protocol that has been published and replicated in multiple prior studies of individuals 
with various neuromuscular diseases.12,14 Briefly, we will use a MI-E device, which is an airway clearance 
device which sits on a flat surface and is connected to corrugated tubing attached to a mouthpiece or mask 
(as per patient preference or for those with bulbar weakness)(Figure 1). To complete the MI maneuver, 
the BiWaze Cough will have preset positive inspiratory pressures and timing to coordinate inhalation 
prior to exhaling (see section 6.1.3 on titration of pressure and timing). After creating a seal with the 
mouthpiece (or mask), an assistant will activate the BiWaze Cough to allow it to perform the preset 
positive pressure inhalation until the subject’s chest is maximally inflated before the subject exhales. This 

 
 
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cycle is repeated 5 times consecutively, concluding the end of one “set”. After a brief break (eg, 30-60 
seconds), the MI maneuver is repeated for another 5 cycles at a time for a total of 5 sets. At the end of 5 
sets, this concludes one MI session. Our protocol includes one MI session (5 sets of 5 inhalations) to be 
performed twice daily.  
 
To determine optimum settings on the BiWaze Cough device for the patient, please refer to Section 
6.1.3. 
Risk/Benefit Assessment 
2.2.5 
Known Potential Risks 
Prior studies on MI have demonstrated that it is well-tolerated without serious adverse 
events.5–11 Performing the insufflation phase of an MI-E device involves inflating a person’s lungs 
to the point of maximal inhalation prior to exhaling.  
The most serious complication from using an MI-E device for applying positive pressure 
using to the lungs includes pneumothorax, or collapsing of a lung. The relative likelihood of this 
is felt to be extremely low, as the use of MI-E is widespread across the world in both the 
inpatient and outpatient setting, yet the occurrence of a pneumothorax related to MI-E is case-
reportable.15–18 In many of the described cases, patients had a comorbidity associated with 
increased likelihood of pneumothorax (eg, chronic obstructive pulmonary disease).  
Accordingly, there are a few potential risks as listed below.  
• Chest wall discomfort or soreness during inflation 
• Increasing volume of air in the chest can slow blood flow to the heart, and thus may 
cause a temporary drop in blood pressure or light-headedness until the subject exhales.  
• Very high inspiratory pressures may increase the likelihood of a pneumothorax (lung 
collapse). 
• The long-term risks of MI are unknown. It is estimated that most of the risks are 
associated with the exercise performance, and thus most risks would be of the immediate 
risk category. 
2.2.6 
Known Potential Benefits 
Given that MI is an exercise in inflating the lungs, it is theorized that mechanisms for benefit 
include12:  
• recruitment of atelectatic alveoli (thus improving gas exchange and airway clearance) 
• improve chest wall range of motion through the sternocostal and costovertebral joints 
(similar to how physical therapy improves joint range of motion) 
• slowing decline of chest wall elasticity by preventing chest wall contractions 

 
 
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Specifically in ALS, volume recruitment of the lungs through techniques such as MI has 
shown short-term improvement in static respiratory measurements such as FVC, peak cough 
flow, volitional airway clearance, and lung compliance.1,19–21  
In alternative neuromuscular diseases (such as Duchenne muscular dystrophy), volume 
recruitment, similar to MI, is believed to slow decline of vital capacity, stabilize lung 
compliance, and maintain effective assisted peak cough flow.3,22 
2.2.7 
Assessment of Potential Risks and Benefits 
The known potential risks associated with MI (as described above) are felt to be low 
likelihood, as supported by multiple prior studies without significant events.5–11 Multiple prior 
studies describe use of MI-E (with the additional use of exsufflation above the insufflation only 
function in this proposal) across a variety of patient populations without significant 
complications.7–9,23–28  
 
We recognize that there are several potential risks with the use of an MI-E device for lung 
insufflation as described above. The most serious of risks includes a pneumothorax, which is felt 
to be extremely rare and a case-reportable event.15–18 
We will mitigate risks through several means: 
1) Individual titration of settings that are tolerated by the patient (see Secton 6.1.3)  
2) MI-E settings allow you to precisely control the level of pressure in the chest, thus 
preventing unmonitored high intrathoracic pressure 
3) Participants will be instructed to stop the insufflation maneuver immediately the moment 
they feel discomfort 
4) We will provide in-person hands-on teaching as well as additional educational material 
via handouts and videos to guide patients in proper procedures 
5) by excluding subjects with certain past medical history: 
• cognitive dysfunction (based on Neurology attendings assessment) that would hinder a 
subject’s ability to complete study procedures 
• craniofacial abnormality will prevent incorrect performance of the MI maneuver 
• the following conditions will lessen likelihood of pneumothorax, low blood pressure, 
incorrect MI performance, or other adverse events associated with transient increase in 
pressure in the chest:  
o Recent hemoptysis 
o Recent barotrauma 
o History or known susceptibility to pneumothorax 

 
 
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o History or known susceptibility to pneumomediastinum 
o History of emphysema of any kind (including bullous emphysema) 
o chronic obstructive pulmonary disease 
o Smoking history of more than 19 pack years (defined as # average cigarettes per day 
while smoking multiplied by the number of years of smoking) 
o Uncontrolled asthma (defined as recent exacerbation requiring corticosteroids in the 
previous 30 days) 
o Symptomatic cardiomyopathy (heart failure) with left ventricular ejection fraction 
less than 50% 
o History of right heart failure or pulmonary hypertension 
o History of recent myocardial infarction or cardiac arrest in the last 90 days 
o Systolic blood pressure less than 90 mmHg 
 
In addition, we will discourage consented individuals from performing MI if any of the 
following scenarios occurring at any time: 
• Immediately after a meal (less than 60 minutes) 
• Symptoms of nausea and vomiting 
• Experiencing chest pain, lightheadedness, or tightness in the chest 
• After trauma to the chest or face (eg, surgery, accidents) 
 
The potential benefits of MI include improved static respiratory measurements such as FVC, 
peak cough flow, volitional airway clearance, and lung compliance. Repeated use over time may 
slow respiratory muscle decline in a progressive neuromuscular disease such as ALS. The 
slowing of decline may prolong time to need for additional respiratory therapy (such as NIV), 
lower likelihood of a respiratory infection, and thus improve quality of life and potentially 
survival. 
ALS is a rapidly progressive neurodegenerative disease without a cure, which commonly 
leads to death by respiratory complications. We are offering MI during a phase of the disease 
that subjects would otherwise receive no respiratory therapies but have already developed 
weakened breathing and coughing. Given that the risks of MI are low, it has been well-tolerated 
in prior studies,5–11 and the risks are minimized by our risk mitigation strategies described above, 
we feel that the potential benefits of MI (and the information gained by the trial) outweigh the 
risks. 

 
 
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3 STUDY OBJECTIVES AND ENDPOINTS 
 
Table 1. Study objectives and endpoints. 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
Primary 
 
 
To determine how the use of twice 
daily MI, in addition to conventional 
treatment, affects decline from baseline 
in PCF (in L/min) over 6 months in 
individuals with early-stage ALS. 
PCF in liters/minute as measured by use 
of a peak flow meter while the patient is 
in a seated upright position.  
An alternative device for measuring PCF 
can be the use of a handheld spirometer 
and using the measured peak expiratory 
flow by multiplying by 60 to convert 
from liters/second to liters/minute. 
The subject must be seated in an upright 
position and the interface must include a 
mouthpiece or an oronasal mask. Subjects 
are asked to perform a deep inhalation 
followed by a maximal cough.  
 
MI is thought to reduce 
chest wall contractures 
and improve volitional 
airway clearance. 
Accordingly, we will 
measure strength of 
airway clearance through 
PCF.  
Secondary 
 
 
To determine how the use of twice 
daily MI over 6 months, in addition to 
conventional treatment, affects 
respiratory strength decline, respiratory 
symptoms, and quality of life. 
Forced vital capacity (FVC) 
o 
Defined as maximal volume, in 
liters, that a person can exhale 
forcefully after a complete 
inhalation. 
o 
Measured using a spirometer 
connected to a face mask or 
mouthpiece in the sitting and 
upright position. 
 
Maximal inspiratory pressure (MIP) 
o 
Defined as the maximum 
pressure, in cmH2O, generated 
when the subject exhales as 
much air as possible and then 
immediately inhales as 
forcefully as possible.  
MI is theorized to slow 
decline of respiratory 
muscle strength and 
respiratory symptoms. 
Accordingly, many of our 
secondary endpoints 
include static respiratory 
strength measurements 
(FVC, MIC, MIC-FVC, 
MIP, MEP), measure of 
ventilation adequacy 
(transcutaneous CO2, 
oxygen saturation), as 
well as assessments of 
respiratory symptoms 
(ALSFRS-R dyspnea and 
orthopnea scores).  
 
 
 
 

 
 
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Table 1. Study objectives and endpoints. 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
o 
Measured using a hand-held 
manual or digital manometer 
connected to a mouthpiece or 
mask in the sitting and upright 
position. 
 
 
 
Maximal expiratory pressure (MEP) 
o 
Defined as the maximum 
pressure, in cmH2O, generated 
when the subject inhales as 
much air as possible and then 
immediately exhales as 
forcefully as possible.  
o 
Measured using a hand-held 
manual or digital manometer 
connected to a mouthpiece or 
mask in the sitting and upright 
position. 
 
 
Maximum insufflation capacity (MIC) 
o 
Defined as exhaled volume, in 
liters, immediately following a 
MI maneuver to maximum 
insufflation capacity. 
o 
Measured using a spirometer 
connected to a face mask or 
mouthpiece, in the sitting and 
upright position. 
 
MIC-assisted PCF 
• 
Defined as the peak cough flow 
generated from MIC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Table 1. Study objectives and endpoints. 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
• 
Lungs are inflated to MIC using 
MI (as above) and before the 
subject exhales they insert a 
peak flow meter in their mouth 
and follow with a peak cough 
flow as described above. 
 
MIC – FVC Difference 
o 
defined by subtracting the FVC 
from the MIC 
 
Transcutaneous carbon dioxide (TCO2) 
and oxygen saturation (SpO2) 
o 
Defined as the average value in 
mmHg from a daytime in-clinic 
measurement over a 15-minute 
transcutaneous recording. 
o 
Measured using a Sentec 
transcutaneous digital 
monitoring system while the 
subject is sitting upright in a 
chair or wheelchair. The 
transcutaneous sensor can be 
placed on the subject forehead, 
cheek, or earlobe.  
o 
The Sentec transcutaneous 
digital monitor measures carbon 
dioxide, oxygen saturation, and 
pulse rate. It is standard of care 
in the Penn ALS clinic and 
would be offered to the patients 
as part of routine clinical care 
regardless of study enrollment. 
 
 
ALSFRS-R dyspnea and orthopnea score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Table 1. Study objectives and endpoints. 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
o 
The ALSFRS-R is a 12-item 
standardized questionnaire to 
assess the motor function status 
of an individual with ALS. The 
ALSFRS-R is assessed by a 
research staff member who has 
been certified for performance of 
the ALSFRS-R.  
o 
The dyspnea score is one of the 
questions focusing on level of 
shortness of breath, scored on a 
scale of 0 to 4, with 4 being no 
symptoms at all and 0 being 
severely symptomatic with 
consideration of mechanical 
respiratory support. 
o 
The orthopnea score is one of the 
questions focused on breathing 
symptoms and difficulty 
sleeping while lying supine, 
scored on a scale of 0 to 4, with 
4 being no symptoms at all and 0 
being severely symptomatic with 
inability to sleep. 
 
Quality of life as measured by 
ALSSQOL-SF, a validated questionnaire 
to assess quality of life in terms 
applicable to a person with ALS. 
o 
The questionnaire includes 20 
questions scored on a scale of 0-
10. 
Global rate of change score for peak 
cough flow 
o 
The global rate of change score 
for the peak cough flow will ask 
patients how effective they think 
their cough is today by rating it 
on a Likert scale from -7 
(extremely impaired) to +7 
(extremely strong). 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If MI attenuates decline 
of respiratory muscle 
strength and symptoms, 
then it may affect quality 
of life. Therefore, we are 
assessing quality of life 
through a standardized 
metric for quality of life 
that has been validated in 
the ALS population. 
 
The effect on MI may 
improve efficacy of 
cough. We are performing 
a global rate of change 
score for peak cough flow 
to compare the subjective 
versus objective change in 
PCF. This may help us 
determine a minimal 
clinically meaningful 
change in PCF.   

 
 
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Table 1. Study objectives and endpoints. 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
Tertiary 
 
 
To determine how the use of twice 
daily MI over 6 months, in addition to 
conventional treatment, can affect time 
to need for additional respiratory 
support or survival. 
Time to start of NIV 
o 
Defined by the time period 
between enrollment for the MI 
trial and start of NIV. 
o 
NIV start date will be defined by 
patient-reported date or as 
documented in the electronic 
medical record. 
 
 
Tracheostomy free survival time 
o 
Defined by the time period 
between enrollment for the MI 
trial and death as long as the 
subject never had a tracheostomy 
placed. 
o 
Death date will be determined by 
family report, electronic medical 
record review, or publicly 
available obituaries. 
o 
Tracheostomy placement will be 
determined by patient or family 
report; or as documented in the 
electronic medical record. 
 
If MI slows respiratory 
function decline, then it 
may slow time to need of 
additional respiratory 
support (such as NIV) or 
even improve survival 
given that respiratory 
failure is the most 
common cause of death in 
ALS.  
  

 
 
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4 STUDY PLAN 
4.1 
Study Design 
This will be a single-center, single-arm interventional pilot study at Penn of MI in patients 
with early-stage ALS who are not yet on alternative respiratory therapy such as NIV or MI-E. 
We hypothesize that individuals who are adherent with MI will have a slower decline in PCF 
compared to matched controls.  
To minimize bias, we will approach all eligible patients and adhere to strict research grade 
protocols for assessing our study endpoints.  
Subject participation will last 6 months, but some endpoints could be collected for up to 6 
months post last study visit.  
4.2 
Scientific Rationale for Study Design 
Given the paucity of data on MI in ALS, a pilot study is necessary prior to implementing a 
RCT. We will compare results of our single arm study to 20 randomly selected matched controls 
from any of the sites of the NIH K23 Philadelphia ALS (PALS) Cohort study. We considered 
“sham MI” (placebo control), however this would be immediately evident to sham subjects and 
thus impossible to blind. A cross-over design is infeasible given the rapidly progressive nature of 
ALS. 
The controls will be matched based on factors 
known to be associated with survival in ALS (eg, 
age, time since disease onset, FVC, bulbar vs spinal 
onset disease). However, using a historical control 
cannot account for all measured and unmeasured 
confounders which can affect a person’s outcome in 
the same manner as a randomized controlled trial. 
As mentioned above, this pilot trial is meant to 
provide hypothesis generating data for a future RCT. 
4.3 
Justification for Dose 
We will use a previously published method to 
perform MI (Figure 2).12,14 The optimum “dose” of 
repetitions and sets to perform the MI maneuver is 
currently unknown. We will follow volume 
recruitment protocol that has been published and 
replicated in multiple prior studies of individuals with neuromuscular disease.5–11 Briefly, we 
will use a MI-E device.  
Figure 2. Performance of MI with BiWaze Cough 
device demonstration on simulated patient. 

 
 
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To complete the MI maneuver, BiWaze Cough will have preset positive inspiratory pressures 
and timing to coordinate a prolonged inhalation at a set pressure prior to the patient exhaling (see 
Section 6.1.3). After creating a seal with the mouthpiece (or mask), an assistant will activate the 
BiWaze Cough to allow it to perform a single positive pressure lung insufflation for 2-3 seconds 
until the subject’s chest is maximally inflated before the subject exhales. The exhalation phase 
lasts for about 2 seconds before a brief pause and then another insufflation is repeated. The 
inhalation for 2-3 seconds and exhalation for 2 seconds is repeated for 5 consecutive cycles. This 
concludes the end of one “set”. After a brief break (eg, 30-60 seconds), the 5-insufflation set is 
repeated again for a total of 5 sets. At the end of 5 sets, this concludes one MI session. Our 
protocol includes one MI session (5 sets of 5 insufflation) to be performed twice daily.  
The duration of insufflation prior to maximum insufflation capacity (MIC) would be 
determined by the patient’s tolerance of the pressure and length of inhalation (as outlined in 
Section 6.1.3). Alternative “doses” of MI, such as more sets or more sessions/day have not been 
studied. We hypothesize that fewer sets or sessions/day may be less likely to provide a 
therapeutic benefit. To our knowledge, no data have tested the dose-specific effect of performing 
more sets or sessions.  
Adherence to the protocol will be tracked using usage data collected by the device. The data 
are uploaded to a cloud-based smartphone app known as “ARC Connect”. Patients will be asked 
to bring in their smartphones with the Arc Connect app for data review at every visit.  
4.4 
End of Study Definition 
A participant is considered to have completed the study if they have completed all phases of 
the study including the last visit or the last scheduled procedure shown in the Schedule of 
Activities (SoA), Appendix Section 12.1. We may collect follow-up data on secondary and 
tertiary clinical outcomes (eg, start of NIV or death) for up to 6 months after last study visit. 

 
 
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5 STUDY POPULATION 
5.1 
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Provision of signed and dated informed consent form. 
2. Age ≥18 years. 
3. Diagnosed with amyotrophic lateral sclerosis using the Gold Coast Criteria.  
4. Have an able and willing caregiver to assist with MI on a daily basis. 
5. Willingness and ability to participate in study procedures. 
 
5.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Age <18 years old. 
2. Inability to perform a cough peak flow or spirometry manuever 
3. Current use of non-invasive ventilation (NIV), bi-level positive pressure ventilation, or “Bi-
PAP” or physician prescribing NIV on day of potential enrollment. 
4. Current use of MI-E (also known as a “cough assist device”) for airway clearance. Please 
note that patients can start use of a MI-E device subsequent to enrollment while currently 
being followed for the study. 
5. Active enrollment in hospice. 
6. Current tracheostomy. 
7. Presence of cognitive dysfunction that would impair ability to complete study procedures, as 
determined by neurology attending physician. 
8. Absence of an able and willing caregiver to assist with MI twice daily as specified in the 
protocol. 
9. Pregnancy 
10. Medical history of:  
a) Recent hemoptysis 
b) Recent barotrauma 
c) History of emphysema of any kind (including bullous emphysema) 
d) History of or known susceptibility to pneumothorax 

 
 
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e) History of or known susceptibility to pneumomediastinum 
f) Chronic obstructive pulmonary disease 
g) Uncontrolled asthma (defined as recent exacerbation requiring corticosteroids in the 
previous 30 days) 
h) Symptomatic cardiomyopathy (heart failure) with left ventricular ejection fraction less 
than 50% 
i) History of right heart failure or pulmonary hypertension 
11. Current smoker or tobacco use within the last 30 days. 
5.3 
Lifestyle Considerations 
Not applicable. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but 
are not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) because 
of an erroneous history based on patient reporting may be rescreened. Rescreened participants 
should be assigned the same participant number as for the initial screening. 
 
5.5 
Strategies for Recruitment and Retention 
The target study sample size for analysis is 20 patients. We anticipate an accrual rate of 50%, 
therefore we will approach up to 40 patients to obtain 20 analyzable subjects. To account for 
study dropouts and withdrawal, we may have to enroll up to 25 participants to obtain 20 
analyzable subjects. 
The source of our participants will include the Penn Comprehensive ALS Center at the 
University of Pennsylvania. 
Potential participants will be identified upon chart review after they are officially diagnosed 
with ALS by one of the attending physician neurologists at the Penn Comprehensive ALS 
Center. Subjects will be screened and approached for interest in the study. Patients will be 
approached during 1 of 3 time periods: 

 
 
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1) At least 2 weeks after their diagnosis visit but in advance of an upcoming routine 
clinical visit with intention of performing a remote consent. 
2) During a routine clinical visit to perform pen and paper consent. 
3) Within 5-14 days after a routine clinical visit with the intention of performing remote 
consent. 
To enhance participant retention over the 6 months of the study, we will collect contact 
information with multiple methods for contacting participants, provide visit reminders as 
necessary, and will provide patient stipends per visit completed throughout the study. 
Inclusion of Children 
ALS is extremely rare in children; therefore, the research topic is essentially irrelevant to 
children (one of the justifiable circumstances for excluding children from a research proposal). 
Age <18 years is an exclusion criterion for the study. Therefore, all individuals in our database 
will be above the age of 18 after enrollment. The proposed study involves minor risk regarding 
patient confidentiality and societal benefits are potentially significant. Because the risks are so 
small and the disease very rarely occurs in children, no specific additional protections for 
children are planned.  
 
Inclusion of Women and Minorities 
No participants will be excluded from study participation based on sex, race, or ethnicity. 
This is appropriate for the model under study, as ALS may impact both sexes as well as all races 
and ethnicities, and selective exclusion could result in bias. The distribution of subjects will 
likely reflect the epidemiology of ALS, which is predominantly a disease of older, white males 
(average age in mid to upper 50’s). The etiology of ALS is currently unknown, and the leading 
theories for this demographic distribution includes genetic and/or environmental factors. The 
Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database is an international, 
multicenter, harmonized database of over 10,000 ALS clinical trial subjects. In PRO-ACT, sex is 
split by 38% females and 62% males, race is divided by about 95% white subjects, 2% black 
subjects, and 3% other races. However, these data could be affected by selective enrollment by 
race due to availability of access to study centers. We will attempt to reach more women and 
minorities in this study by approaching women and minorities whenever they are eligible. We 
also plan future studies of MI or NIV in early ALS at external academic referral centers in the 
Philadelphia area, which are likely to have significant demographic and socioeconomic diversity 
from one another. This study has no specific exclusions based on sex, race, or ethnicity. 
 
 

 
 
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6 STUDY INTERVENTION 
6.1 
Study Intervention(s) Administration 
6.1.1 
Study Intervention Description 
The BiWaze Cough device includes several components as shown in Figure 3: 
1) BiWaze Cough System 
2) BiWaze Cough Standard Breathing Circuit 
o 22 mm bacterial/viral filter 
o Corrugated tubing 
o Patient Interface (Anesthesia mask [small, medium or large] or Mouthpiece) 
3) Nose clip 
4) Carrying Bag 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Figure 3. BiWaze Cough system (panel A) and ABM Respiratory carrying bag 
(panel B). 
1 
2a-2c 
2d 
3 
A 

 
 
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Table 2. The BiWaze Cough device components. 
Item 
number in 
Figure 3 
Name of 
Device 
Manufacturer 
Description 
Marketing 
Status in 
the U.S. 
FDA Device 
Classification  
(I, II, III) 
1 
BiWaze 
Cough 
System 
 
BC20113 
ABM 
Respiratory Care 
Standard USA (includes control 
unit, internal battery, carrying bag, 
English user manual, power cord, 
filter adapter, single path circuit) 
 510k 
Clearance 
(K191912) 
II 
2a 
BiWaze 
Cough 
Standard 
Circuit – 
Adult Small 
Face Mask 
 
BC21088 
ABM 
Respiratory Care 
 
Standard adult small patient circuit 
(includes single path breathing 
tube, adapter, bacterial/viral filter, 
adult small face mask) 
 
None 
2b 
BiWaze 
Cough 
Standard 
Circuit – 
Adult 
ABM 
Respiratory Care 
Standard adult medium patient 
circuit (includes single path 
breathing tube, adapter, 
bacterial/viral filter, adult medium 
face mask) 
 
None 
B 
4 

 
 
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Medium 
Face Mask 
 
BC21089 
2c 
BiWaze 
Cough 
Standard 
Circuit – 
Adult Large 
Face Mask 
 
BC21273 
ABM 
Respiratory Care 
Standard adult large patient circuit 
(includes single path breathing 
tube, adapter, bacterial/viral filter, 
adult large face mask) 
 
None 
2d 
BiWaze 
Cough 
Standard 
Circuit – 
Mouthpiece 
 
BC21092 
ABM 
Respiratory Care 
Standard mouthpiece patient circuit 
(includes single path breathing 
tube, adapter, bacterial/viral filter, 
mouthpiece 
 
None 
3 
Nose Clips 
w/Foam Pads 
McKesson 
Model: 16-MCKNC 
 
None 
4 
BiWaze 
Carrying bag  
 
BC21083 
ABM 
Respiratory Care 
Soft sided carrying bag with ABM 
Respiratory Care logo 
 
None 
6.1.2 
Dosing and Administration 
We will use a previously published method to perform MI.12,14 The optimum “dose” of 
repetitions and sets to perform the MI maneuver is currently unknown. According to prior 
studies, MI is performed as a “therapy session” according to the following “dose” for all 
patients throughout the study: 
o Using an MI-E device, deliver MI as one prolonged inhalation until maximal lung 
expansion, after which the mask/mouthpiece if removed and the subject performs 
passive exhalation. This inhalation/exhalation cycle is repeated 5 times. This constitutes 
one “set”.  
o After each set, the subject takes a break for 30-60 seconds before repeating the MI 
maneuver.  
o The MI maneuver and break is repeated as above for 5 sets.  
 
The above described “therapy session” is repeated twice daily. Instructions for 
determination of settings are found below under Section 6.1.3 “Instructions for initial set-up 
and determining optimum pressure, timing, and flow settings”. 

 
 
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The timing of the MI is ideally done on an empty stomach (at least 30 minutes prior to or 90 
minutes after a meal) to allow for maximal chest expansion without incurring diaphragm 
restriction against a full stomach. 
If the subject misses a dose, then the subject should attempt to perform an MI therapy session 
as soon as possible before or after their next meal (at least 30 minutes prior or 90 minutes after a 
meal). If the subject misses a therapy session at the end of a day, then the subject may perform a 
therapy session prior to bedtime.  
If a subject realizes in hindsight that they missed a therapy session on the previous day, then 
performing a “make-up” session on the following day (ie, 3 sessions in one day) is not necessary. 
In that scenario, the subject is encouraged to continue performing MI twice daily as regularly 
scheduled. 
 
6.1.3 
Instructions for initial set-up and determining optimum pressure, timing, 
and flow settings: 
To determine optimum insufflation pressure and program a MI setting for the patient, we will 
follow the following titration protocol with BiWaze Cough: 
• Ensure the patient interface is secure 
o If using a mouthpiece, ensure patient can form a tight seal around the 
mouthpiece in a manner that is unlikely to leak with applied inhalation 
pressure 
o If using a face mask, ensure the face mask can create a tight seal on the 
patients face around the bridge of the nose and around the sides/bottom of the 
mouth. There are 3 face mask sizes available to ensure optimal fit. 
• In manual mode, Titrate the inhalation pressure. Start with an inspiratory pressure 
of +20 cmH2O for timing of 2 seconds  
• Set the exhalation pressure to 0 cmH2O for 0 seconds.  
• Set the pause pressure of +5 cmH2O and timing for 2 seconds.  
• Increase inhalation pressure in 5 cmH2O increments to visible maximal chest rise 
while avoiding patient discomfort based upon patient feedback. A patient’s comfort 
level and patient interface will influence the final inhalation pressure.  
• Do not increase the inhalation pressure beyond +50 cmH2O.  
• The subject will receive an inhalation during the inhalation phase and will be taught 
to exhale during the pause phase before the next breath. 
 
To determine optimum insufflation time duration: 
o Once a comfortable inhalation pressure is identified, determine length of inhalation by re-
trialing inhalation times by starting at 2.0 seconds and doing consecutive inhalation trials 
after increasing in 0.5 second increments to a maximum of 4.0 seconds.  

 
 
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o After determining inhalation time, determine pause timing by starting at 2.0 seconds and 
doing consecutive trials of inhalation/exhalation to assess for patient tolerance of 
exhalation time. Increase/decrease pause timing for exhalation in 0.5 second increments 
up to a minimum of 1.0 seconds and a maximum of 3.0 seconds. 
 
To determine optimum insufflation flow setting: 
o The rate of flow of air can be adjusted to patient comfort. The options are slow, medium, 
or fast. 
o Start at a medium flow setting and assess for patient comfort with the speed of air entry 
by asking if the air is coming in too fast or too slow.  
o Adjust the air flow to low or fast as necessary depending on patient answer above.  
o Note that patients with significant bulbar weakness may require a low inhalation flow 
setting. 
 
Setting the desired program into the device: 
• Program Auto mode to deliver 5 consecutive cycles of insufflation/pause for 
exhalation breathes at the desired pressure and timing as determined above.  
• Save this programmed therapy as a profile with a name “MI”. 
• The subject can use this Auto mode to do sets of the 5 cycle MI session with 30 – 60 
second breaks between each set.  
 
 
Final MI session will be performed as follows: 
Using the MI preset in Auto mode after determining above pressure and timing titrated to patient 
comfort: 
1. Insufflation breath at +20-50 cmH2O for 2-4 seconds followed by an exhalation 
phase for 1-3 seconds at +5 cmH2O 
2. Insufflation breath at +20-50 cmH2O for 2-4 seconds followed by an exhalation 
phase for 1-3 seconds at +5 cmH2O 
3. Insufflation breath at +20-50 cmH2O for 2-4 seconds followed by an exhalation 
phase for 1-3 seconds at +5 cmH2O 
4. Insufflation breath at +20-50 cmH2O for 2-4 seconds followed by an exhalation 
phase for 1-3 seconds at +5 cmH2O 
5. Insufflation breath at +20-50 cmH2O for 2-4 seconds followed by an exhalation 
phase for 1-3 seconds at +5 cmH2O 
  
Pause and then rest ~30 – 60 seconds and then repeat for a total of 5 sets. 
  
Perform above protocol twice daily. 
 
 

 
 
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6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Acquisition and accountability 
BiWaze Cough systems will be loaned for this study from ABM Respiratory Care, LLC: 
ABM Respiratory Care, LLC 
860 Blue Gentian Road 
Suite 200 
Eagan, MN, 55121-1567 
 
The company contact is: 
Leah Noaeill 
VP of Marketing and Clinical Affairs 
ABM Respiratory Care 
Leah.Noaeill@abmrc.com  
612.419.1071  
www.abmrc.com 
 
The BiWaze Cough will be mailed to the Penn Comprehensive ALS Clinic at: 
Penn Neurologic Institute  
330 S. 9th Street 
Room 310 
Philadelphia, PA 19107 
Once the devices have been delivered, they will be distributed by the PI and/or research staff at 
the Penn Comprehensive ALS Clinic. 
If any of the BiWaze Cough systems appear unusable for any reason (eg, damaged in shipment), 
then the devices will be rendered unusable until a replacement device or part has been obtained 
from ABMRC, LLC.  
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
There will be no modification of the appearance, packaging, or labeling of the BiWaze Cough 
prior to distribution to the study subject. 
6.2.3 
Product Storage and Stability 
The BiWaze Cough is an FDA 510k cleared device made of medical grade materials. Whether it 
is in the Penn Comprehensive ALS Clinic or the patient’s home the recommended storage 
location is in a temperature-controlled room so as to avoid extreme heat or cold.  

 
 
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BiWaze Cough does not expire unless one of the components is misplaced or becomes damaged. 
Cleaning instructions: 
Subjects will be instructed to clean the mouthpiece/mask and tubing least once per week. 
Subjects will be asked to clean the equipment more often if they have a cold or chest infection.  
 
The instructions for cleaning will include:  
o Disconnect the mouthpiece/mask and tubing from the BiWaze Cough.  
o Separate the mouthpiece/mask from the tubing.   
o Gently clean the tubing and mouthpiece/mask in mild soap and water. Rinse in warm 
water.  
o Allow parts to completely dry before use. Do not use a hairdryer to dry the equipment. 
 
6.2.4 
Preparation 
BiWaze Cough ships with all necessary components as listed in Table 2. The research 
subjects will go home with the BiWaze Cough in a travel bag included with the system. Note that 
patients will still have the option of exchanging the mouthpiece with the anesthesia mask if 
bulbar weakness prevents a proper seal on the mouthpiece.  
6.3 
Measures to Minimize Bias: Randomization and Blinding 
This is a single center, single arm study. We do not plan to implement any blinding or 
randomization.  
We will minimize selection bias by approaching all eligible patients.  
We will ensure measurement accuracy by implementing strict quality assurance/quality 
control procedures. The center involved in this study has significant prior experience with 
enrollment for clinical trials. The assessments and procedures used (eg, spirometry performance) 
will be performed according to ALS clinical trial grade standards.29 Pulmonary function testing 
results will be calculated using American Thoracic Society guideline equations.30  
 
6.4 
Study Intervention Compliance 
Adherence to MI therapy sessions will be recorded on the BiWaze Cough system in the 
subject’s home. BiWaze Cough stores the data in an encrypted log file which can be sent via 
WiFi to an online, HIPPA complaint data repository platform called ARC Connect (ABM 
Respiratory Care, USA). The clinicians can access the usage data through a secure online ARC 
Connect portal and review the subject’s compliance to the MI therapy. 
Reports will include: date/time of use, number of inhalation/exhalation cycles, number of sets 
of insufflation/exhalation cycles, and pressure used. 

 
 
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ARC Connect’s data privacy policy states that it does collect the following personal 
information: 
• 
Name 
• 
Email Address 
• 
Phone Number 
 
To help protect subject privacy: we will create subject accounts with altered contact 
information for each subject’s profile in ARC Connect as follows: 
Title  
 
 
 
 
 
 
 
Will be changed to: 
• 
Name  --------------------------à  
Subject ID number 
• 
Email Address -----------------à        An @pennmedicine account for research staff 
• 
Phone Number  --------------à       The Penn ALS clinic research staff mobile number  
 
We will review usage reports with subjects at the research study visits.  
6.5 
Concomitant Therapy 
For this protocol, subjects will be allowed to be on concomitant respiratory therapies as 
indicated by standard of care. Examples of concomitant respiratory therapies include the use of 
non-invasive ventilation (NIV), mechanical insufflation-exsufflation (MI-E) therapy, or airway 
clearance therapy with inhalers and/or inhaled nebulized medication (eg, albuterol).  
We will assess for concomitant respiratory therapies at each visit (baseline and follow-up) 
throughout the study. We will record therapy start date as reported by the patient/caregiver or via 
review of electronic medical record. Usage of NIV or MI-E (with the additional exsufflation 
function) may also be confirmed via remote telemonitoring data if the patient is set-up for this 
service through the durable medical equipment (DME) company. 
It is possible that concomitant use of respiratory therapies may confound the effect of MI. To 
account for this, we will ensure accurate recording of start dates (via means stated above), 
confirm usage of concomitant therapies by telemonitoring (if available), and ensure strict 
clinical-trial-grade measurements of our endpoints. 
6.5.1 
Rescue Medicine 
Not applicable. 

 
 
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7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
Discontinuation from MI use does not mean discontinuation from the study, and remaining 
study procedures should be completed as indicated by the study protocol. If a clinically 
significant finding is identified (including, but not limited to changes from baseline) after 
enrollment, the investigator or qualified designee will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an adverse event 
(AE). 
The data to be collected at the time of study intervention discontinuation will include the 
following: 
• Subjects will be asked to come into the clinic as scheduled to perform assessments as 
described in the study protocol. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
• Pregnancy 
• Significant MI non-compliance, as defined by failure to use MI for more than 4 weeks. 
• If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant 
• Disease progression which requires discontinuation of MI 
• If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation (eg, hospice enrollment) 
• Participant unable to receive MI for 4 weeks or more 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
MI-PALS Case Report Form (CRF). Subjects who sign the informed consent form and 
subsequently withdraw, or are withdrawn or discontinued from the study, will be replaced by 
another subject. 

 
 
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7.3 
Lost To Follow-Up 
A participant will be considered lost to follow-up if he or she fails to return for more than 2 
scheduled visits and is unable to be contacted by the study site staff for more than 60 days. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site will attempt to contact the participant and reschedule the missed visit within 4 
weeks and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file.  
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 

 
 
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8 STUDY ASSESSMENT AND PROCEDURES 
8.1 
Efficacy Assessments 
Primary endpoint: 
o Peak cough flow (PCF) 
 
Secondary endpoints: 
o Forced vital capacity (FVC) 
o Maximal inspiratory pressure (MIP) 
o Maximal expiratory pressure (MEP) 
o Maximum insufflation capacity (MIC) 
o MIC-assisted PCF 
o MIC-FVC difference 
o Transcutaneous carbon dioxide (TCO2) and pulse oximetry (SpO2) 
o ALSFRS-R 
o Global rate of change score for PCF 
 
Tertiary endpoints:  
o Start date of non-invasive ventilation 
o Tracheostomy free survival time 
 
8.1.1 
Peak cough flow (PCF) 
PCF will be measured by use of a peak flow meter while the patient is in a seated upright 
position. The peak flow meter will be connected to a mouthpiece or anesthesia mask if the 
subject has too much bulbar weakness to create a sufficient mouth seal on the mouthpiece. 
An alternative device for measuring PCF can be the use of a handheld spirometer and using the 
measured peak expiratory flow by multiplying by 60 to convert from liters/second to 
liters/minute. 

 
 
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8.1.2 
Forced vital capacity (FVC) 
Measured using a hand-held clinical-research grade spirometer connected to a mouthpiece in the 
sitting and upright position. An anesthesia mask may be used in place of a mouthpiece if the 
subject has too much bulbar weakness to create a sufficient mouth seal on the mouthpiece. 
Defined as maximal volume, in liters, that a person can exhale forcefully after a complete 
inhalation.  
 
8.1.3 
Maximal inspiratory pressure (MIP) 
Measured using a hand-held manual or digital manometer connected to a mouthpiece or mask in 
the sitting and upright position. 
Defined as the maximum pressure, in cmH2O, generated when the subject exhales as much air as 
possible and then immediately inhales as forcefully as possible.  
 
8.1.4 
Maximal expiratory pressure (MEP) 
Measured using a hand-held manual or digital manometer connected to a mouthpiece or mask in 
the sitting and upright position. 
Defined as the maximum pressure, in cmH2O, generated when the subject inhales as much air as 
possible and then immediately exhales as forcefully as possible.  
 
 
8.1.5 
Maximum insufflation capacity (MIC) 
Measured using a hand-held clinical-research grade spirometer connected to a mouthpiece in the 
sitting and upright position. An anesthesia mask may be used in place of a mouthpiece if the 
subject has too much bulbar weakness to create a sufficient mouth seal on the mouthpiece. 
Defined as exhaled volume, in liters, immediately following a MI maneuver to maximum 
insufflation capacity. 
 
8.1.6 
MIC-assisted Peak Cough Flow  
MIC-FVC difference will be obtained by asking the subject to perform a peak cough flow (as 
described above) from the MIC.  
 
 

 
 
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8.1.7 
MIC-FVC difference 
MIC-FVC difference will be obtained by subtracting the FVC from the MIC.  
8.1.8 
Transcutaneous carbon dioxide (TCO2) and oxygen saturation (SpO2) 
Measured using a Sentec transcutaneous digital monitoring system while the subject is sitting 
upright in a chair or wheelchair. The transcutaneous sensor can be placed on the subject 
forehead, cheek, or earlobe.  
Defined as the average value in mmHg (TCO2) or in percentage of saturated hemoglobin (SpO2) 
from a daytime in-clinic measurement over a 15-minute transcutaneous recording. 
The Sentec transcutaneous digital monitor measures carbon dioxide, oxygen saturation, and 
pulse rate. It is standard of care in the Penn ALS clinic and would be offered to the patients as 
part of routine clinical care regardless of study enrollment. 
 
 
8.1.9 
Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised 
(ALSFRS-R) dyspnea and orthopnea scores 
The ALSFRS-R is a 12-item standardized questionnaire to assess the motor function status of an 
individual with ALS. It is a validated assessment used as part of standard of care and all clinical 
trials for ALS. The ALSFRS-R is assessed by a research staff member who has been certified for 
performance of the ALSFRS-R.  
Specifically, the dyspnea score is one of the questions focusing on level of shortness of breath, 
scored on a scale of 0 to 4, with 4 being no symptoms at all and 0 being severely symptomatic 
with consideration of mechanical respiratory support. 
The orthopnea score is one of the questions focused on breathing symptoms and difficulty 
sleeping while lying supine, scored on a scale of 0 to 4, with 4 being no symptoms at all and 0 
being severely symptomatic with inability to sleep. 
8.1.10 
Global rate of change score for cough peak flow  
The global rate of change score for cough peak flow will obtain a participant’s subjective sense 
of efficacy of their cough. The global rate of change score for the cough peak flow will ask 
patients how effective they think their cough is today by rating it on a Likert scale from -7 
(extremely impaired) to +7 (extremely strong). 
 

 
 
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8.1.11 
Start date of non-invasive ventilation (NIV) 
NIV start date will be defined by patient-reported date or as documented in the electronic 
medical record. 
Defined by the time period between enrollment for the MI trial and start of NIV. 
 
8.1.12 
Tracheostomy-free survival time and death date 
Death date will be determined by family report, electronic medical record review, or publicly 
available obituaries. To determine tracheostomy-free survival time, tracheostomy placement will 
be determined by patient or family report; or as documented in the electronic medical record. 
 
8.1.13 
ARC Connect data collection 
Each subject will have daily usage data collected from the ARC Connect smartphone app. The 
usage data will be collected via reports from the app which will be downloaded at each clinical 
visit. The usage reports will include device usage data such as date/time of use, number of 
inhalation cycles, number of sets of inhalation cycles, and pressure used. 
 
 
8.2 
Safety and Other Assessments 
8.2.1 
Consent 
Consent will be obtained for enrollment from participants. For each consent process, study 
personnel will discuss the details of the study, the risks and benefits, and the subject’s rights and 
responsibilities if they choose to participate in the trial and their right to refuse to participate.  It 
will be made clear that their clinical care will not be affected by their decision.   
8.2.2 
Institutional Review Board process 
Study staff will obtain IRB approval before any study procedures are initiated. 
8.2.3 
Screening and enrollment 
Study staff will screen participants who are seen at the study center and have a diagnosis of 
amyotrophic lateral sclerosis based on Gold Coast Criteria.31 
Screening must occur within 3 months of enrollment.  
The screening process will involve review of electronic medical records to review inclusion and 
exclusion criteria.  

 
 
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Eligible subjects will be approached either via telephone or during a routine clinic visit to the 
study center. When approaching patients, study staff will again confirm inclusion and exclusion 
criteria. Study staff will discuss a brief overview of the study. If the potential subject is 
interested, then the informed consent process will begin (see Section 10.1.1 “Informed Consent 
Process”).  
8.2.4 
Medical history 
Medical history will be obtained through both a) speaking to a consenting subject and b) review 
of electronic medical records. 
8.2.5 
Physical exam 
A physical exam will be performed by an attending physician. For the purposes of this study, it 
will either be a board-certified neurologist or pulmonologist.  
8.2.6 
Vital signs 
Routine vital signs will be obtained by trained medical personnel. 
8.2.7 
Study assessments 
Study assessments will be performed during study visits as described in Section 12.1 Schedule 
of Activities. Electronic medical record review and questionnaires will be performed by study 
staff who have Collaborative Institutional Training Initiative (CITI) training in human subjects 
research. Pulmonary function testing will be performed by qualified personnel trained to perform 
testing in accordance with clinical trial standards.29 Results of all study assessments will be 
discussed with subjects. 
8.2.8 
Education of study intervention  
Consenting subjects will be provided with a BiWaze cough device. Study staff will provide in-
person hands-on training in performance of MI using the BiWaze cough device. Subjects will 
also receive additional education via MI performance both in writing and videos. Study staff will 
call subjects periodically to address any concerns or questions.  
8.2.9 
Assessment of study intervention adherence 
Adherence to MI therapy sessions will be recorded on the BiWaze Cough system in the 
subject’s home. BiWaze Cough stores the data in an encrypted log file which can be sent via 
WIFI to an online, HIPPA compliant data repository platform called Arc Connect (ABM 
Respiratory Care, USA). The clinicians can access the usage data through a secure online Arc 
Connect portal and review the subject’s compliance to the MI therapy.  
Reports will include: date/time of use, number of inhalation/exhalation cycles, number of sets 
of inhalation/exhalation cycles, and pressure used. 

 
 
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8.2.10 
Assessment of adverse events 
The use of MI in neuromuscular disease has been well tolerated without significant adverse 
event across multiple prior studies.5–11 
 
We will avoid discontinuing MI for clinical events not thought to be serious MI-related AEs. 
For example, a hospitalization for clinical worsening will not result in cessation of trial 
participation. Such events could result in missing data for primary and secondary endpoints, 
comprising the integrity of the analysis. As the trial does not prohibit any therapies which are the 
standard of care in ALS, there is no ethical or safety reason to stop trial participation under such 
circumstances. Even if subjects are withdrawn from MI, outcome assessments will continue, 
allowing analysis by intent-to-treat.  
 
8.3 
Adverse Events and Serious Adverse Events 
8.3.1 
Definition of Adverse Events (AE) 
An adverse event (AE) is any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention related. Intercurrent illnesses or 
injuries should be regarded as adverse events. 
A pre-existing condition should be recorded as an adverse event if the frequency, intensity or the 
character of the condition changes. 
8.3.2 
Definition of Serious Adverse Events (SAE)  
Serious Adverse Events (SAE) 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that, 
in the view of either the investigator or the sponsor, is: 
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• an important medical event when the event does not fit the other outcomes, but the event 
may jeopardize the patient and may require medical or surgical intervention (treatment) 
to prevent one of the other outcomes. 
• required intervention to prevent permanent impairment or damage (for devices only) 
Important medical events are those that may not be immediately life threatening but are clearly 
of major clinical significance. They may jeopardize the subject and may require intervention to 

 
 
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prevent one of the other serious outcomes noted above. For example, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department 
would typically be considered serious. All AEs that do not meet any of the criteria for serious 
should be regarded as non-serious AEs. 
8.3.3 
Unanticipated Adverse Device Effect (UADE) 
Unanticipated Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety, or any life-threatening problem or 
death caused by, or associated with, a device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the investigational plan or application, or 
any other unanticipated serious problem associated with a device that relates to the rights, safety, 
or welfare of subjects. 
8.3.4 
Classification of an Adverse Event 
8.3.4.1 
Severity of Event 
For adverse events (AEs) not included in the protocol defined grading system, the following 
guidelines will be used to describe severity. 
• Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities.  
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. Of note, the term “severe” does not necessarily equate to “serious”. 
8.3.4.2 
Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to MI assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below. In a 
clinical trial, the study product must always be considered. 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to MI administration and 
cannot be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of MI (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory 
rechallenge procedure if necessary. 

 
 
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• Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of MI, is unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (dechallenge). Rechallenge information is not 
required to fulfill this definition. 
• Possibly Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related”, as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to MI administration makes a causal relationship improbable 
(e.g., the event did not occur within a reasonable time after administration of MI) and in 
which other drugs or chemicals or underlying disease provides plausible explanations 
(e.g., the participant’s clinical condition, other concomitant treatments). 
• Unrelated – The AE is completely independent of MI administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the clinician. 
8.3.4.3 
Expectedness  
The medical monitor will be responsible for determining whether an adverse event (AE) is 
expected or unexpected. An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described for MI. 
8.3.5 
Time Period and Frequency for Event Assessment and Follow-Up 
Safety will be assessed by monitoring and recording potential adverse effects using the grading 
system described above for adverse events (Definitely, probably, possibly, unlikely, or 
unrelated), at each study visit. Participants will be monitored by medical histories, physical 
examinations, and chart review. If the above-mentioned grading system does not apply for an 
adverse event, the severity of mild, moderate, severe, life-threatening, and death, corresponding 
to Grades 1-5, will be used whenever possible. 
At each contact with the subject, the investigator will seek information on adverse events by non-
directive questioning and, as appropriate, by examination. Adverse events may also be detected 
when they are volunteered by the subject during the screening process or between visits, or 
through physical examination, laboratory test, or other assessments. Information on all adverse 
events will be recorded in the source documentation. To the extent possible, adverse events will 

 
 
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be recorded as a diagnosis and symptoms used to make the diagnosis recorded within the 
diagnosis event. 
As much as possible, each adverse event or follow-up information will be evaluated to 
determine: 
1. Severity grade (CTCAE Grade 1-5) 
2. Duration (start and end dates) 
3. Relationship to the study treatment or process – [Reasonable possibility that AE is 
related: No (unrelated/ not suspected) or Yes (a suspected adverse reaction)]. If yes 
(suspected) - is the event possibly, probably or definitely related to the investigational 
treatment? 
4. Expectedness to study treatment or process – [Unexpected – if the event severity and/or 
frequency is not described in the investigator brochure (if applicable) or protocol]. 
5. Action taken with respect to study or investigational treatment or process (none, dose 
adjusted, temporarily interrupted, permanently discontinued, unknown, not applicable) 
6. Whether medication or therapy taken (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
7. Whether the event is serious 
Once an adverse event is detected, it should be followed until its resolution or until it is judged to 
be permanent, and assessment should be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
Unsolicited adverse events will be captured within case report forms for each study visit. 
Information collected on unsolicited adverse events will be collected as described above for 
adverse events. 
Solicited adverse events will include targeted questions at each visit regarding the use of MI: 
• Chest discomfort 
• Dizziness 
• Lightheadedness 
• Sudden worsening shortness of breath 
Data on solicited adverse events will also be captured within the case report form. 
We will plan our data reporting system to avoid double capture of unsolicited and solicited 
adverse events. 

 
 
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Solicited and unsolicited adverse events will be assessed throughout study duration and follow-
up after initiating the intervention (ie, days 0 through 180 for 6 months of follow-up). 
8.3.6 
Adverse Event Reporting 
Reporting Period 
Adverse events will be reported from the time of informed consent until study completion. 
Investigator Reporting: Notifying the Study Sponsor 
Every non-fatal SAE, regardless of suspected causality (e.g., relationship to study product(s) or 
study procedure(s) or disease progression) must be reported to the sponsor within 15 calendar 
days of learning of its occurrence. 
Fatal or life-threatening SAEs which are probably or definitely related to death must be reported 
to the IRB and study sponsor (Jason Ackrivo) within 3 calendar days.  
Serious and unexpected AEs which are fatal or life-threatening must be reported within 7 days to the 
NIH NHLBI.  
Recurrent episodes, complications, or progression of the initial SAE must be reported to the 
Sponsor as a follow-up to the original episode within 10 business days of the investigator 
receiving the follow-up information. A SAE considered completely unrelated to a previously 
reported one should be reported separately as a new event. 
Send the SAE report to the local IRB and NIH NHLBI. 
New information regarding the SAE will be reported as it becomes available and in the same 
manner that the initial SAE (i.e. SAE form). The investigator must follow the event to resolution 
or until the event is deemed and documented irreversible, whichever is longer. 
Disease-related events which would be expected in ALS include: 
• Pneumonia 
• Worsening shortness of breath 
• Mucus plugging 
• Weakness 
• Fatigue 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the 
Clinical Investigator’s study file. 
 

 
 
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Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the Penn 
IRB using the institution required form or as a written report of the event (including a description of 
the event with information regarding its fulfillment of the above criteria, follow-up/resolution and 
need for revision to consent form and/or other study documentation).  
The Primary Investigator is expected to provide as much of the following information as is available:  
• 
Protocol name and number  
• 
Subject identifiers  
• 
Demographic data  
• 
Nature of the event  
• 
Severity of the event  
• 
Probable relationship (causality) of AE to study procedure  
• 
Date and time of AE onset Date and time of AE resolution, if available  
• 
Concomitant medications that the participant was taking for an underlying medical condition 
or disease and the therapeutic agents used for the treatment of the adverse event Clinical 
assessment of participant conducted at time of SAE/AE  
• 
Results of any laboratory and/or diagnostic procedures, and treatment  
• 
Follow-up plan  
• 
Outcome  
• 
Autopsy findings (if appropriate)  
 
The Principal Investigator and research coordinator will provide details about the AE as they become 
available. If additional information cannot be obtained for whatever reason, this will be documented.  
 
The Principal Investigator should promptly determine an assessment of causality.  
 
The Principal Investigator/designee should keep originals or photocopies of all relevant 
documentation, including facsimile confirmations and email exchanges, and file them in the 
participant's file.  
 
The Principal Investigator/designee should file copies of all correspondence with the IRB in the 
appropriate section of the Regulatory Master File or site study file. 
 
 
 
 

 
 
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Investigator Reporting: Local Reporting Requirements 
The investigator will report AEs and SAEs to the IRB/EC of record and other local regulatory 
groups per the local requirements. 
8.3.7 
Serious Adverse Event Reporting  
The study clinician will immediately report to the sponsor any serious adverse event, whether or 
not considered MI related, including those listed in the protocol or investigator brochure and 
must include an assessment of whether there is a reasonable possibility that MI caused the event. 
Study endpoints that are serious adverse events (e.g., all-cause mortality) must be reported in 
accordance with the protocol unless there is evidence suggesting a causal relationship between 
MI and the event (e.g., death from pneumothorax). In that case, the investigator must 
immediately report the event to the sponsor. 
New information regarding the SAE will be reported as it becomes available and in the same 
manner that the initial SAE (i.e. SAE form). All serious adverse events (SAEs) will be followed 
until satisfactory resolution or until the site investigator deems the event to be chronic or the 
participant is stable. Other supporting documentation of the event may be requested by the Data 
Coordinating Center (DCC)/study sponsor and should be provided as soon as possible. 
The SAE reports to the Sponsor should be sent to: Jason Ackrivo, MD, MSCE at the contact 
information listed in Section 1.2 Key Roles and Study Governance.  
The study sponsor will be responsible for notifying the NIH and IRB of any unexpected fatal or 
life-threatening suspected adverse reaction per applicable regulations. In addition, the sponsor 
must notify NIH and all participating investigators of potential serious risks, from clinical trials 
or any other source, as per the applicable regulation. 
The study investigator shall complete an Unanticipated Adverse Device Effect Form and submit 
to the study sponsor and to the reviewing Institutional Review Board (IRB) within 10 working 
days. The study sponsor is responsible for conducting an evaluation of an unanticipated adverse 
device effect and shall report the results of such evaluation to the IRB, NIH, and Food and Drug 
Administration (FDA), (as applicable) and to all reviewing IRBs and participating investigators 
per the applicable regulation. 
8.3.8 
Reporting Events to Participants  
Any AEs related to MI will likely occur at the time of or shortly after use of MI. Therefore, 
participants will likely be aware of the AE and will most likely be the primary source of AEs. 
8.3.9 
Events of Special Interest  
Any device malfunction would likely be related to the integrity of the components in the BiWaze 
cough device. Participants may report a device issue (eg, malfunctioning device, crack in the 
corrugated tubing) to the research staff. If the BiWaze cough device or its accessory components 

 
 
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(tubing, mask, etc) are deemed to be defective beyond simple repair, then the participant will be 
provided with a replacement device or accessory component within 2 weeks.  
8.3.10 
Reporting of Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE. When a pregnancy has been confirmed in a 
subject, and the fetus is exposed to the physiologic effects of MI, then the research staff will 
withdrawal the subject from the study. Any data collected up to and including the day of 
pregnancy notification can still be used in the final analysis. The subject may continue to use MI 
at the discretion of the attending physician. 
8.4 
Unanticipated Problems 
8.4.1 
Definition of Unanticipated Problems (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
8.4.2 
Unanticipated Problem Reporting 
Unanticipated problems (UPs) such as: 
• 
Post-marketing withdrawal of a drug, device, or biologic used in a research protocol due 
to safety concerns. 
• 
FDA ban of a drug, device, or biologic used in a research protocol due to safety concerns. 
• 
Complaint of a participant when the complaint indicates unexpected risks, or the 
complaint cannot be resolved by the research team 
• 
Breach of confidentiality 
• 
Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the subject to remain on 
the study 

 
 
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• 
Premature closure of a study (e.g., due safety, lack of efficacy, feasibility, financial 
reasons, etc.) 
should be reported by the investigator to the Sponsor, reviewing Institutional Review Board 
(IRB) and to the lead principal investigator (PI). The UP report will include the following 
information: 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• A detailed description of the event, incident, experience, or outcome;  
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP; 
• A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline: 
• UPs that are serious adverse events (SAEs) will be reported as any other SAE. 
• UPs that are not SAEs must be reported to the NHLBI, the IRB, and/or DCC within 14 
days of the investigator becoming aware of the problem. All UPs that are not SAEs must 
be reported within 30 days to OHRP by the Penn IRB. 
• All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), and 
the Office for Human Research Protections (OHRP) within 30 days of the IRB’s receipt 
of the report of the problem from the investigator. 
8.4.3 
Reporting Unanticipated Problems To Participants  
Any UPs related to MI will likely occur at the time of or shortly after use of MI. Therefore, 
participants will likely be aware of the AE and will most likely be the primary source of AEs. 
8.5 
Device Reporting 
Safety reporting for the device(s) will be according to 21 CFR 812.150.] 
 

 
 
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9 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
Our null hypothesis is in individuals with ALS there is no difference in peak cough flow between 
those who use MI versus those who do not use MI over 6 months. 
Our primary endpoint is change in peak cough flow over 6 months compared to baseline. 
 
Our Secondary Efficacy Endpoint(s) will be change in the following endpoints over 6 months: 
• Forced vital capacity 
• Maximal inspiratory pressure 
• Maximal expiratory pressure 
• Maximum insufflation capacity 
• Maximum insufflation capacity minus vital capacity 
• Maximum insufflation capacity assisted peak cough flow 
• ALSFRS-R total score 
• ALSFRS-R dyspnea score 
• ALSFRS-R orthopnea score 
• Partial pressure of transcutaneous carbon dioxide  
• Oxygen saturation 
• Global rate of change score for peak cough flow 
 
Our tertiary endpoints include: 
• Time to start of non-invasive ventilation 
• Tracheostomy-free survival time 
 
 
9.2 
Sample Size Determination 
Our outcome measure use for calculations is the change in peak cough flow (PCF).  
 
We will base our calculations on results from the following study: 

 
 
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Kaminska M, Browman F, Trojan DA, Genge A, Benedetti A, Petrof BJ. Feasibility of Lung 
Volume Recruitment in Early Neuromuscular Weakness: A Comparison Between 
Amyotrophic Lateral Sclerosis, Myotonic Dystrophy, and Postpolio Syndrome. PM&R 
2015;7:677–684. 
 
Primary endpoint: 
PCF: 
 
In the study listed above, the ALS group had a change in PCF of (mean, 95% CI): -25.0 (-58.4, 
8.4) L/min. This corresponds to a mean, standard deviation (SD) of -25 ± 26.9 L/min. 
 
A mean ± SD of -25 ± 26.9 L/min can determine an effect size of 0.669 with a change in the 
mean by -18 to -43 L/min with the same SD of 26.9.  
 
Assuming the effect size of 0.669, we estimate that 20 subjects will provide 80% power to detect 
a difference in PCF of at least 18 L/min with a SD of 26.9.  
 
Secondary endpoints (selected): 
FVC: 
Assuming an effect size of 0.413, we estimate that 20 subjects will provide 42% power to detect 
a difference in FVC of 0.16 with SD of 0.387. 
 
MIC: 
Assuming an effect size of 0.451, we estimate that 20 subjects will provide 48% power to detect 
a difference in MIC of 0.188 with SD 0.417 using a two-tail t-test.  
 
To obtain 20 subjects, assuming a 50% consent rate, we will approach 40 eligible patients. To 
attain 40 eligible patients, we will screen 60 total patients with incident diagnoses of ALS.  
 
While there is adequate power to detect clinically important differences, the main purpose of this 
study is to obtain effect estimates in order to assist with the design of future larger studies. 
9.3 
Populations for Analyses 
This is a single arm study of MI. We will screen, approach, and enroll subjects seen for 
regularly-scheduled clinic visits at the University of Pennsylvania Penn Comprehensive ALS 
center.  
We will compare our findings to 20 matched control subjects who do not use MI who are 
enrolled for longitudinal data collection portion of the Philadelphia ALS (PALS) Cohort study. 
The PALS cohort study routinely collects peak cough flow (our primary endpoint) and select 
secondary/tertiary endpoints such as: FVC, ALSFRS-R scores, ALSSQOL-SF scores, time to 
start of non-invasive ventilation, and tracheostomy-free survival time.   

 
 
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9.4 
Statistical Analyses 
9.4.1 
General Approach 
Descriptive statistics will include mean ± standard deviation for parametric distributed variables 
and median (interquartile range for 25th, 75th percentile) for non-parametric distributed variables. 
 
Hypothesis testing will use a two-sided α= 0.05 without correction for multiplicity. We will 
summarize demographics along with baseline and follow-up primary and secondary endpoints.  
 
We will characterize subjects with regard to baseline and follow-up primary and secondary 
endpoints. We will summarize demographics and other predictors of clinical status. Continuous 
variables will be summarized by the mean, median, standard deviation, and range, as appropriate. 
We will use contingency tables for discrete and dichotomous variables.  
 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) 
 
Our primary endpoint is decline from baseline in peak cough flow (PCF) over 6 months in 
individuals with early-stage ALS who have yet to start respiratory therapies. PCF is a continuous 
variable. 
PCF is measured in in liters/minute. It is measured via use of one of 2 devices:  
1) a peak flow meter while the patient is in a seated upright position. The patient is asked to 
inhale as deep as possible, then create a tight seal on the flow meter with their mouth, and 
then cough as quickly and forcefully as possible through the flow meter. 
2) a handheld spirometer using the measured peak expiratory flow output. The technique is 
similar as described above for the peak flow meter. After completion of the maneuver, 
the peak expiratory flow is typically reported in L/seconds, and can be converted to peak 
cough flow units by multiplying by 60 to convert from liters/second to liters/minute. 
To compare our intervention arm to the matched controls, we will compare means with unpaired 
two-tailed t-tests or Wilcoxon rank sum tests.  
 
9.4.2.1 
Missing data 
We will attempt to minimize missing data, however we have planned for its occurrence. For 
subjects lost to follow-up, we will use all of the information available until the end of follow-up. 
 

 
 
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This protocol will continue to follow and perform test procedures as described even if a subject 
drops-out from the therapeutic portion of the study. That is, if a subject decides that he/she does 
not wish to continue with MI, the subject will stop the investigational treatment, but will still be 
strongly encouraged to continue to follow-up with the study personnel for all scheduled study 
procedures (e.g., peak cough flow, spirometry, etc.), so that missing data (and assumptions 
regarding these data) will be minimized. 
 
9.4.3 
Analysis of the Secondary Endpoint(s) 
All secondary endpoints will be measured as described in Section 3, Study Objectives and 
Endpoints.  
• Forced vital capacity is a continuous variable in Liters or as a percent of predicted normal 
compared to age, sex, and height-matched controls. 
• Maximal inspiratory compacity – vital capacity difference is a continuous variable in 
Liters. 
• Maximal inspiratory pressure is a continuous variable in cmH2O.  
• Maximal expiratory pressure is a continuous variable in cmH2O.  
• ALSFRS-R total score is a continuous variable reported as an integer.  
• ALSFRS-R dyspnea score is an ordinal variable on a scale of 0, 1, 2, 3, or 4. 
• ALSFRS-R orthopnea score is an ordinal variable on a scale of 0, 1, 2, 3, or 4. 
• Global rate of change in peak cough flow is a Likert scale from -7 to +7. 
• Partial pressure of transcutaneous carbon dioxide is a continuous variable measured in 
mmHg. 
• Oxygen saturation is a continuous variable measured in % saturation of hemoglobin. 
• Time to start of non-invasive ventilation is a continuous variable measured in days. 
• Tracheostomy-free survival time is a continuous variable measured in days. 
 
Exploratory multivariate analyses will be performed incorporating all of the available endpoint 
assessments (baseline, 2 months, 4 months, and six months) in an ANCOVA model with active 
treatment/control status as the independent variable. 
 

 
 
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9.4.4 
Safety Analyses 
All subjects will be assessed in the safety analysis. This analysis will include summary statistics 
of any adverse events. Safety interim analyses will be performed and reported to the medical 
monitor after subjects 5, 10, and 15 have completed study participation.  
 
Subjects will be evaluated for SAEs. 
 
Serious adverse events or events leading to premature discontinuation of study participation will 
be in the form of a table as follows: 
 
Subject 
ID 
Adverse 
event 
Start 
date 
Stop 
date 
Duration Severity Relationship Expectedness Outcome 
 
 
 
 
 
 
 
 
 
 
9.4.5 
Baseline Descriptive Statistics 
Baseline description variables will be separated by intervention arm (MI) and control (no MI) 
groups.  
 
Variables will include: 
• Age 
• Sex at birth 
• Race (patient-reported) 
• Body mass index 
• Diagnosis delay time between symptom onset and date of diagnosis 
• Symptom onset site 
• Forced vital capacity % predicted 
• ALS Functional Rating Scale – Revised total score 
• ALS Functional Rating Scale – Revised dyspnea score 
• ALS Functional Rating Scale – Revised orthopnea score 
• Smoking history 
• Comorbidities 

 
 
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9.4.6 
Planned Interim Analyses  
Not applicable. 
9.4.7 
Sub-Group Analyses 
Analysis of the primary and secondary endpoints will also be analyzed by the following 
subgroups: 
• Symptom onset site (limb versus bulbar) 
9.4.8 
Exploratory Analyses 
Not applicable. 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Informed Consent Process 
10.1.1.1 
Consent/Assent and Other Informational Documents Provided To 
Participants 
Consent forms describing MI in detail, study procedures, and risks are given to the participant 
and written documentation of informed consent is required prior to starting MI. The following 
consent materials are submitted with this protocol: 
• Informed consent document 
• Telephone script for remote consenting 
• One-page flyer advertising trial 
10.1.1.2 
Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
Institutional Review Board (IRB)-approved and the participant will be asked to read and review 
the document. The investigator will explain the research study to the participant and answer any 
questions that may arise. A verbal explanation will be provided in terms suited to the 
participant’s comprehension of the purposes, procedures, and potential risks of the study and of 
their rights as research participants. Participants will have the opportunity to carefully review the 
written consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with their family or surrogates or think about it prior to agreeing 
to participate. The participant will sign the informed consent document prior to any procedures 

 
 
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being done specifically for the study. Participants must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. A copy of 
the informed consent document will be given to the participants for their records. The informed 
consent process will be conducted and documented in the source document (including the date), 
and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
Consent will be obtained for enrollment from participants. Each study center will have the option 
of obtaining informed consent either in-person (pen and paper hard-copy signed consent) or via 
remote consent.   
Remote consent 
Remote consenting will be performed in advance of an eligible subject’s regularly scheduled 
clinical visit and prior to any data collection. 
 
At the University of Pennsylvania Penn Comprehensive ALS clinic, remote consent will be 
performed using REDCap. Eligible subjects will receive a phone call from the research 
coordinator in advance of their regularly scheduled clinic visit. The research coordinator will use 
a remote consent script to introduce themselves, describe the reason for the call, introduce the 
research, and ask whether the eligible subject is interested in hearing more about the study. If the 
eligible subject is interested in the study, then the research coordinator will send the subject a 
survey link via e-mail/text message that leads to a REDCap survey which contains an electronic 
copy of the latest IRB-approved and stamped informed consent form. While the eligible subject 
views the electronic consent, the research coordinator will read the consent to the patient over the 
telephone. If an eligible subject consents to participation, their consent will be documented via 
electronic signature within the REDCap survey e-consent. After signing, REDCap offers subjects 
the opportunity to download an electronic PDF version of the signed consent. Alternatively, the 
research coordinator can offer to provide the subject a hard copy of the signed consent by either 
a) mailing to the subject’s home or b) providing a signed copy during a clinical visit.  
 
As a reference, remote consenting procedures will mimic the procedures outlined in the Penn 
IRB guidance for remote consenting document located at the following link: 
 
https://irb.upenn.edu/wp-content/uploads/2023/02/PM-Guidance-on-Remote-Consent-
Procedures.pdf 
 
For each consent process, study personnel will discuss the details of the study, the risks and 
benefits, and the subject’s rights and responsibilities if they choose to participate in the study and 
their right to refuse to participate. It will be made clear that their clinical care will not be affected 
by their decision. 
 

 
 
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Each subject will have ample time and opportunity to ask questions and will be informed about 
the right to withdraw from the study at any time without any disadvantage and without having to 
provide reasons for this decision. 
 
Only if the subject voluntarily agrees to sign the ICF and has done so, may they enter the study. 
Additionally, the investigator and other information provider (if any) will personally sign and 
date the form. The subject will receive a copy of the signed and dated form for the main study 
(clinical data collection). 
 
The signed informed consent statement (and verbal consent documentation to the semi-structured 
interview) are to remain in the investigator site file or, if locally required, in the patient’s 
note/file of the medical institution. 
 
The ICF and any other written information provided will be revised whenever important new 
information becomes available that may be relevant to the subject’s consent, or there is an 
amendment to the protocol that necessitates a change to the content of the subject information 
and/or the written ICF. The investigator will inform the subject of changes in a timely manner 
and will ask the subject to confirm his/her willingness to continue participation. Any revised 
written ICF and written information must receive the IRB’s approval / favorable opinion in 
advance of use. 
 
10.1.2 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated by the Sponsor or the PI at 
any site if there is sufficient reasonable cause. Written notification, documenting the reason for 
study suspension or termination, will be provided by the suspending or terminating party to the 
study participants, investigator, NIH NHLBI, and the IRB. If the study is prematurely terminated 
or suspended, the Principal Investigator (PI) will promptly inform study participants, the 
Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the termination 
or suspension. Study participants will be contacted, as applicable, and be informed of changes to 
study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or are not evaluable 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor and/or IRB. 

 
 
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In terminating the study, the Sponsor and the Principal Investigator will assure that adequate 
consideration is given to the protection of the subjects’ interests. 
10.1.3 
Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
the clinical information relating to participants. Therefore, the study protocol, documentation, 
data, and all other information generated will be held in strict confidence. No information 
concerning the study or the data will be released to any unauthorized third party without prior 
written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), regulatory agencies or pharmaceutical company supplying 
study product may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to 
such records. 
The study participant’s contact information will be securely stored for internal use during the 
study. At the end of the study, all records will continue to be kept in a secure location for as long 
a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored within REDCap. This will not include the 
participant’s contact or identifying information. Rather, individual participants and their research 
data will be identified by a unique study identification number. The study data entry and study 
management systems used by clinical sites and by University of Pennsylvania Penn 
Comprehensive ALS Center research staff will be secured and password protected. At the end of 
the study, all study databases will be de-identified and archived within REDCap and stored at the 
Penn Comprehensive ALS Center at the University of Pennsylvania. 
 
Telemonitoring protection of privacy: 
Adherence to MI therapy sessions will be recorded on the BiWaze Cough system in the 
subject’s home. BiWaze Cough stores the data in an encrypted log file which can be sent via 
WIFI to an online, HIPPA compliant data repository platform called Arc Connect (ABM 
Respiratory Care, USA). The clinicians can access the usage data through a secure online Arc 
Connect portal and review the subject’s compliance to the MI therapy.  
Reports will include: date/time of use, number of inhalation/exhalation cycles, number of sets 
of inhalation/exhalation cycles, and pressure used. 

 
 
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ARC Connect’s data privacy policy states that it does collect the following personal 
information: 
• 
Name 
• 
Email Address 
• 
Phone Number 
 
To help protect subject privacy: we will create subject accounts with altered contact 
information for each subject’s profile in ARC Connect as follows: 
Title  
 
 
 
 
 
 
 
Will be changed to: 
• 
Name  --------------------------à  
Subject ID number 
• 
Email Address -----------------à        An @pennmedicine account for research staff 
• 
Phone Number  --------------à       Penn ALS clinic research staff mobile number  
 
Certificate of Confidentiality (if applicable) 
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued 
by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants. 
10.1.4 
Future Use of Stored Specimens and Data  
Data collected for this study will be analyzed and stored within REDCap and at the Penn 
Comprehensive ALS Center at the University of Pennsylvania. After the study is completed, the 
de-identified, archived data will be transmitted to and stored within REDCap and at the Penn 
Comprehensive ALS Center at the University of Pennsylvania, for use by other researchers 
including those outside of the study. Permission to transmit data to REDCap will be included in 
the informed consent. 
When the study is completed, access to study data and/or samples will be provided through 
REDCap. 
10.1.5 
Safety Oversight 
Safety oversight will be under the direction of a Medical Monitor who is an individual with the 
appropriate expertise, including pulmonary care of individuals with chronic respiratory failure. 

 
 
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The Medical Monitor should be independent from the study conduct and free of conflict of 
interest, or measures should be in place to minimize perceived conflict of interest. The Medical 
Monitor will meet at least semiannually to assess safety and efficacy data on each arm of the 
study. The Medical Monitor will operate under the rules of an approved charter. At this time, 
each data element that the Medical Monitor needs to assess will be clearly defined. The Medical 
Monitor will provide its input to the study sponsor, Dr. Jason Ackrivo, MD, MSCE. 
 
10.1.6 
Clinical Monitoring 
Site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct 
of the trial is in compliance with the currently approved protocol/amendment(s), with 
International Conference on Harmonization Good Clinical Practice (ICH GCP), and with 
applicable regulatory requirement(s). 
• Monitoring for this study will be performed by the PI and a Medical Monitor. 
• On-site monitoring will occur monthly by the PI and semi-annually by the Medical 
Monitor in a targeted fashion.  
• A Medical Monitor will be provided copies of monitoring reports on a semi-annual basis. 
• Details of clinical site monitoring are documented in a Data Safety Monitoring Plan 
(DSMP). The DSMP describes in detail who will conduct the monitoring, at what 
frequency monitoring will be done, at what level of detail monitoring will be performed, 
and the distribution of monitoring reports. 
• Independent audits or compliance reviews may be conducted by a Medical Monitor semi-
annually to ensure monitoring practices are performed consistently across all 
participating sites and that monitors are following the DSMP. 
 
10.1.7 
Quality Assurance and Quality Control 
All monitoring and audits are to be performed according to ICH GCP E6(R2). 
The Penn Comprehensive ALS Center at the University of Pennsylvania will be the only clinical 
site for this study. The Penn Comprehensive ALS Center will perform internal quality 
management of study conduct, data collection, documentation, and completion. An 
individualized quality management plan will be developed to describe a site’s quality 
management.  
There will be a Investigator Initiation meeting prior to any subject enrollment to review study 
procedures, measurements, data collection, record keeping, and data entry expectations. The PI 

 
 
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will train the appropriate research staff (eg, research coordinator, nurse practitioner, physicians) 
on proper MI technique and methods for teaching patients/caregivers. Staff training will be 
tracked using Staff Training Log and Delegation of Responsibilities Log. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. The PI will perform QA and 
QC checks by reviewing case report forms, REDCap data, and clinical records such as EMR 
clinic notes and spirometry reports. PI review of data quality will occur at least every 3 months, 
or more frequently, if necessary. Any missing data or data anomalies will be communicated to 
the research coordinators and other research staff (as applicable) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated, documented (recorded), and reported in 
compliance with the protocol, International Conference on Harmonization Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices 
(GLP), Good Manufacturing Practices (GMP)). 
The Penn Comprehensive ALS Center will provide direct access to source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
10.1.8 
Data Handling and Record Keeping  
10.1.8.1 
Data Collection and Management Responsibilities  
Data collection is the responsibility of the clinical trial staff at the Penn Comprehensive ALS 
Center under the supervision of the PI. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data and follow ALCOAC standards (attributable, legible, contemporaneous, 
original, accurate, and complete). 
Hardcopies of the study visit worksheets (case report forms) will be provided for use as source 
document worksheets for recording data for each participant enrolled in the study. Data recorded 
into REDCap derived from source documents should be consistent with the data recorded on the 
source documents. 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) will be entered into REDCap, a 21 CFR Part 11-compliant data capture system 
provided by the University of Pennsylvania. The data system includes password protection and 
internal quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents. 

 
 
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10.1.8.2 
Study Records Retention  
Study documents should be retained for at least 2 years have elapsed since the formal 
discontinuation of MI. These documents should be retained for a longer period, however, if 
required by local regulations. No records will be destroyed without the written consent of the 
sponsor, if applicable. It is the responsibility of the sponsor to inform the investigator when these 
documents no longer need to be retained. 
10.1.9 
Protocol Deviations 
Protocol deviations are not allowed. The PI will review data entry within REDCap at least every 
3 months to monitor for protocol deviations. The PI and the study team should document all 
scenarios where the protocol is not followed and provide, in particular: 
• Who deviated from the protocol 
• What was the deviation 
• When did the deviation occur 
• How did the deviation happen 
• What is the impact of the deviation 
• A root cause analysis of why the deviation occurred 
If the assessment results in a determination that any of the following are potentially affected, the 
deviation would be considered of significant impact: 
• having the potential to adversely affect subject safety; OR 
• increases risks to participants; OR 
• adversely affects the integrity of the data; OR 
• violates the rights and welfare of participants, OR 
• affects the subject’s willingness to participate in research.  
• there is a potential for an overall impact on the research that should be shared with the 
IRB for consideration and development of next best steps to address it. 
10.1.10 
Publication and Data Sharing Policy 
Full details of a publication policy will be described in the study MOP. The Penn Comprehensive 
ALS Center at the University of Pennsylvania is the only site in the study, therefore a data use 
agreement is unnecessary.   

 
 
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10.1.11 
Conflict of Interest Policy 
As of this writing, no study staff involved in this study have an active conflict of interest with 
BiWaze or any other respiratory device company. BiWaze is providing these devices in-kind as a 
loan for the duration of the study. The independence of this study from any actual or perceived 
influence, such as by respiratory device companies, is critical. Therefore, any actual conflict of 
interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of 
this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of 
interest will be required to have such conflicts managed in a way that is appropriate to their 
participation in the design and conduct of this trial. 
10.2 Additional Considerations 
Not applicable. 
10.3 Protocol Amendment History 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by the sponsor, Dr. Jason Ackrivo. A protocol change intended to eliminate an 
apparent immediate hazard to subjects may be implemented immediately, provided the IRB/IEC 
is notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment. The written 
amendment must be submitted to the IRB/IEC and the investigator must await approval before 
implementing the changes. The sponsor, Dr. Jason Ackrivo, will submit protocol amendments to 
the appropriate regulatory authorities. 
If in the judgment of the sponsor (Dr. Jason Ackrivo) the IRB/IEC, and/or the investigator, the 
amendment to the protocol substantially changes the study design and/or increases the potential 
risk to the subject and/or has an impact on the subject's involvement as a study participant, the 
currently approved written informed consent form will require similar modification. In such 
cases, informed consent will be renewed for subjects enrolled in the study before continued 
participation. 
The table below is intended to capture changes of IRB-approved versions of the protocol, 
including a description of the change and rationale.  
 
Version 
Date 
Description of Change  
Brief Rationale 
1 
11.27.23 
Initial submission 
 
 
 
 

 
 
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11 REFERENCES 
1. Kaminska M, Browman F, Trojan DA, Genge A, Benedetti A, Petrof BJ. Feasibility of Lung 
Volume Recruitment in Early Neuromuscular Weakness: A Comparison Between Amyotrophic 
Lateral Sclerosis, Myotonic Dystrophy, and Postpolio Syndrome. PM&R. 2015;7:677–684. 
2. Katz SL, Barrowman N, Monsour A, Su S, Hoey L, McKim D. Long-Term Effects of Lung 
Volume Recruitment on Maximal Inspiratory Capacity and Vital Capacity in Duchenne 
Muscular Dystrophy. Annals of the American Thoracic Society. 2016;13:217–222. 
3. McKim DA, Katz SL, Barrowman N, Ni A, LeBlanc C. Lung volume recruitment slows 
pulmonary function decline in Duchenne muscular dystrophy. Archives of physical medicine and 
rehabilitation. 2012;93:1117–1122. 
4. Chiou M, Bach JR, Jethani L, Gallagher MF. Active lung volume recruitment to preserve vital 
capacity in Duchenne muscular dystrophy. Journal of rehabilitation medicine. Epub 2016. 
5. Mustfa N, Aiello M, Lyall RA, et al. Cough augmentation in amyotrophic lateral sclerosis. 
Neurology. 2003;61:1285–1287. 
6. Chatwin M, Bush A, Simonds AK. Outcome of goal-directed non-invasive ventilation and 
mechanical insufflation/exsufflation in spinal muscular atrophy type I. Arch Dis Child. 
2011;96:426. 
7. Vianello A, Corrado A, Arcaro G, et al. Mechanical Insufflation–Exsufflation Improves 
Outcomes for Neuromuscular Disease Patients with Respiratory Tract Infections. American 
Journal of Physical Medicine & Rehabilitation. 2005;84:83–88. 
8. Miske LJ, Hickey EM, Kolb SM, Weiner DJ, Panitch HB. Use of the Mechanical In-
Exsufflator in Pediatric Patients With Neuromuscular Disease and Impaired Cough. Chest. 
2004;125:1406–1412. 
9. Tzeng AC, Bach JR. Prevention of Pulmonary Morbidity for Patients With Neuromuscular 
Disease. Chest. 2000;118:1390–1396. 
10. Bach JR, Gonçalves MR, Hamdani I, Winck JC. Extubation of Patients With Neuromuscular 
Weakness. Chest. 2010;137:1033–1039. 
11. Vitacca M, Paneroni M, Trainini D, et al. At Home and on Demand Mechanical Cough 
Assistance Program for Patients With Amyotrophic Lateral Sclerosis. Am J Phys Med Rehab. 
2010;89:401–406. 

 
 
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12. Chatwin M, Toussaint M, Gonçalves MR, et al. Airway clearance techniques in 
neuromuscular disorders: A state of the art review. Resp Med. 2018;136:98–110. 
13. Miller R, Jackson C, Kasarskis E, et al. Practice Parameter update: The care of the patient 
with amyotrophic lateral sclerosis: Drug, nutritional, and respiratory therapies (an evidence-
based review) Report of the Quality Standards Subcommittee of the American Academy of 
Neurology. Neurology. 2009;73:1218–1226. 
14. Sawnani H, Mayer OH, Modi AC, et al. Randomized trial of lung hyperinflation therapy in 
children with congenital muscular dystrophy. Pediatr Pulmonol. 2020;55:2471–2478. 
15. McDonald LA, Berlowitz DJ, Howard ME, Rautela L, Chao C, Sheers N. Pneumothorax in 
neuromuscular disease associated with lung volume recruitment and mechanical insufflation‐
exsufflation. Respirol Case Rep. 2019;7:e00447. 
16. Westermann EJA, Jans M, Gaytant MA, Bach JR, Kampelmacher MJ. Pneumothorax as a 
complication of lung volume recruitment* **. J Bras Pneumol. 2012;39:382–386. 
17. Suri P, Burns SP, Bach JR. Pneumothorax Associated with Mechanical Insufflation–
Exsufflation and Related Factors. Am J Phys Med Rehabilitation. 2008;87:951–955. 
18. Loewen AHS, Tye R, Rimmer KP, Fraser KL. Pneumothorax in chronically ventilated 
neuromuscular and chest wall restricted patients: A case series. Can J Respir, Crit Care, Sleep 
Med. 2018;2:200–204. 
19. Cleary S, Misiaszek JE, Kalra S, Wheeler S, Johnston W. The effects of lung volume 
recruitment on coughing and pulmonary function in patients with ALS. Amyotroph Lat Scl Fr. 
2013;14:111–115. 
20. Cleary S, Misiaszek JE, Wheeler S, Kalra S, Genuis SK, Johnston WS. Lung volume 
recruitment improves volitional airway clearance in amyotrophic lateral sclerosis. Muscle Nerve. 
2021;64:676–682. 
21. Lechtzin N, Shade D, Clawson L, Wiener CM. Supramaximal inflation improves lung 
compliance in subjects with amyotrophic lateral sclerosis. Chest. 2006;129:1322–1329. 
22. Katz SL, Mah JK, McMillan HJ, et al. Routine lung volume recruitment in boys with 
Duchenne muscular dystrophy: a randomised clinical trial. Thorax. 2022;77:805–811. 
23. Gomez-Merino E, Bach JR. Duchenne Muscular Dystrophy. Am J Phys Med Rehabilitation. 
2002;81:411–415. 

 
 
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24. Bach JR, Baird JS, Plosky D, Navado J, Weaver B. Spinal muscular atrophy type 1: 
management and outcomes. Pediatr Pulmonol [online serial]. 2002;34:16–22. Accessed at: 
https://www.ncbi.nlm.nih.gov/pubmed/12112792. 
25. Bach J. Amyotrophic Lateral Sclerosis Prolongation of Life by Noninvasive Respiratory 
Aids. Chest. 2002;122:92–98. 
26. Bach JR, Kang S-W. Disorders of Ventilation Weakness, Stiffness, and Mobilization. Chest. 
2000;117:301–303. 
27. BECK GJ, SCARRONE LA. Physiological Effects of Exsufflation with Negative Pressure 
(E.W.N.P.). Dis Chest. 1956;29:80–95. 
28. Winck JC, Gonçalves MR, Lourenço C, Viana P, Almeida J, Bach JR. Effects of Mechanical 
Insufflation-Exsufflation on Respiratory Parameters for Patients With Chronic Airway Secretion 
Encumbrance. Chest. 2004;126:774–780. 
29. Brinkmann J, Andres P, Mendoza M, Sanjak M. Guidelines for the use and performance of 
quantitative outcome measures in ALS clinical trials. Journal of the neurological sciences. 
1997;147:97–111. 
30. Stanojevic S, Kaminsky DA, Miller MR, et al. ERS/ATS technical standard on interpretive 
strategies for routine lung function tests. Eur Respir J. 2022;60:2101499. 
31. Shefner JM, Al-Chalabi A, Baker MR, et al. A Proposal for New Diagnostic Criteria for 
ALS. Clin Neurophysiol. 2020;131:1975–1978. 
32. Molgat-Seon Y, Hannan LM, Dominelli PB, et al. Lung volume recruitment acutely 
increases respiratory system compliance in individuals with severe respiratory muscle weakness. 
ERJ open research. 2017;3. 
33. Srour N, LeBlanc C, King J, McKim DA. Lung volume recruitment in multiple sclerosis. 
PloS one. 2013;8:e56676. 
  
 
 
 
 

 
 
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12 APPENDIX  
12.1  Schedule of Activities (SoA) 

 
 
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Procedures 
Screening 
Day -7 to -1 
Enrollment/ 
Baseline 
Vi it 1 D
1
Study Visit 2  
Day 60  +/-14 
d
Study Visit 3 
Day 120 +/- 14 
days
Final Study 
Visit 4 
Day 180 +/-14 
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Contact information 
X 
X 
 
 
 
Medical history 
X 
X 
 
 
 
Social history 
X 
X 
 
 
 
Respiratory history 
 
X 
 
 
 
MI teaching and technique review 
 
X 
X 
X 
X 
Review MI usage data on ARC Connect app 
 
X 
X 
X 
X 
Concomitant medication review 
<~~~~~~~~~~~~~~~~X~~~~~~~~~~~~~~~~> 
Physical exam (including height and weight) 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
Height 
X 
 
 
 
 
Weight 
X 
X 
X 
X 
ALS symptoms and history 
X 
 
 
Peak cough flow (PCF) 
 
X 
X 
X 
X 
Forced vital capacity (FVC) 
X 
X 
X 
X 
Maximal inspiratory pressure 
X 
X 
X 
X 
Maximal expiratory pressure 
 
X 
X 
X 
X 
Maximal insufflation capacity (MIC) 
 
X 
X 
X 
X 
MIC-assisted PCF 
 
X 
X 
X 
X 
MIC – FVC Difference 
 
X 
X 
X 
X 
Transcutaneous carbon dioxide and oxygen saturation 
 
X 
X 
X 
X 
ALS Functional Rating Scale-Revised scores 
 
X 
X 
X 
X 
Global rate of change score for peak cough flow 
 
X 
X 
X 
X 
Outcomes assessment (tertiary endpoints)  
 
 
X 
X 
X 
Adverse event review and evaluation 
 
<~~~~~~~~~~~X~~~~~~~~~~~> 
Complete Case Report Forms (CRFs) 
X 
X 
X 
X 
X 
 

 
 
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END OF DOCUMENT