Stacking Exercises Attenuate the Decline in Forced Vital Capacity and Sick Time (STEADFAST)
Phase: PHASE4
Conditions: Duchenne Muscular Dystrophy
Sponsor: Children's Hospital of Eastern Ontario

Stacking Exercises Attenuate the Decline in Forced Vital Capacity and Sick Time 
(STEADFAST) 
Katz 
 
Jesse’s Journey 2013 
Protocol Version_ Extension Amendment 3_4 June 2015 
 
1
 
 
 
 
 
Title: Stacking Exercises Attenuate the Decline in Forced Vital Capacity 
and Sick Time (STEADFAST) 
 
Funded By: Jessie’s Journey the foundation for Gene and Cell therapy 
 
Registered: Clinicaltrials.gov #NCT01999075 
 
Current Protocol Version: 
Extension Amendment 3  4 June 2015 
Replaces previous version : 
Extension Amendment 2_24 Oct 2013 
 
Extension Amendment 1_24 July 2013 
 
5 February 2013 
 
 
 
 
 
 
 

Stacking Exercises Attenuate the Decline in Forced Vital Capacity and Sick Time 
(STEADFAST) 
Katz 
 
Jesse’s Journey 2013 
Protocol Version_ Extension Amendment 3_4 June 2015 
 
2
TABLE OF CONTENTS 
SCIENTIFIC ABSTRACT .......................................................................................................................... 3 
LAY LANGUAGE SUMMARY OF PROJECT ....................................................................................... 4 
LAY LANGUAGE DESCRIPTION OF PROJECT DISSEMINATION/ KNOWLEDGE 
TRANSFER STRATEGIES ........................................................................................................................ 4 
DETAILED PROJECT PROPOSAL ......................................................................................................... 5 
BACKGROUND DATA .......................................................................................................................... 5 
REVIEW OF THE LITERATURE ....................................................................................................... 5 
RATIONALE FOR THE PROJECT ..................................................................................................... 5 
HYPOTHESIS/RESEARCH QUESTIONS .......................................................................................... 7 
Primary Question: ................................................................................................................................ 7 
Secondary Questions: .......................................................................................................................... 7 
SPECIFIC OBJECTIVES ...................................................................................................................... 7 
PROJECT DESIGN AND RESEARCH METHODOLOGY .............................................................. 7 
1. PROPOSED TRIAL DESIGN & INTERVENTIONS ................................................................... 7 
2.  ALLOCATION OF PARTICIPANTS TO TRIAL GROUPS ........................................................ 9 
3 METHODS FOR PREVENTING BIAS .......................................................................................... 9 
4.  INCLUSION/EXCLUSION CRITERIA ........................................................................................ 9 
5. FREQUENCY AND DURATION OF FOLLOW-UP ...................................................................10 
6. PRIMARY AND SECONDARY OUTCOME MEASURES ..........................................................10 
7.  SAMPLE SIZE AND JUSTIFICATION ......................................................................................10 
8. PLANNED RECRUITMENT RATE .............................................................................................11 
9. ADHERENCE .................................................................................................................................11 
10.  ANALYSIS PLAN ........................................................................................................................11 
PILOT STUDIES ................................................................................................................................12 
TIMELINE/MILESTONES ..................................................................................................................13 
STEERING COMMITTEE AND DATA SAFETY MONITORING BOARD .................................13 
ACRONYMS ...........................................................................................................................................15 
ANTICIPATED IMPACT/RELEVANCE TO DUCHENNE MUSCULAR DYSTROPHY ................16 
REFERENCES .......................................................................................................................................17 
APPENDICES .............................................................................................................................................24 
APPENDIX 1- LVR SET-UP WITH DATA LOGGER ...........................................................................24 
APPENDIX 2. LVR PILOT DATA .......................................................................................................25 
APPENDIX 3. SURVEY DATA .............................................................................................................26 
APPENDIX 4. LIST OF STUDY SITES & LETTERS OF SUPPORT ............................................................27 
APPENDIX 5: STUDY FLOW DIAGRAM & STUDY ACTIVITIES ...............................................28 
APPENDIX 6. LUNG VOLUME RECRUITMENT TECHNIQUE FOR THERAPISTS ................31 
APPENDIX 7. DATA-LOGGER TO MONITOR ADHERENCE ......................................................33 
APPENDIX 8. RESCUE TREATMENT...............................................................................................34 
APPENDIX 9:   JUSTIFICATION FOR CO-VARIATES IN MINIMIZATION ANALYTICAL MODEL ..............35 
APPENDIX 10: RESPIRATORY SYMPTOM QUESTIONNAIRE .................................................36 
APPENDIX 11: LVR SATISFACTION QUESTIONNAIRE ............................................................38 
APPENDIX 12 SELF-REPORT USAGE QUESTIONNAIRE ...........................................................40 
APPENDIX 13: PEDSQL GENERIC CORE ..............................................................................................42 
APPENDIX 14:–ADVERSE EVENT DEFINITIONS .........................................................................43 
APPENDIX 15: CASE REPORT (DATA COLLECTION) FORM ...................................................44 
 
 
 

Stacking Exercises Attenuate the Decline in Forced Vital Capacity and Sick Time 
(STEADFAST) 
Katz 
 
Jesse’s Journey 2013 
Protocol Version_ Extension Amendment 3_4 June 2015 
 
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SCIENTIFIC ABSTRACT  
Keywords: 
Duchenne muscular dystrophy, pulmonary complications, lung volume recruitment, 
breath-stacking, cough efficacy, maximal insufflation capacity 
Detailed Summary (up to 450 words) 
Background: Respiratory complications are the primary cause of morbidity and 
mortality associated with childhood Duchenne Muscular Dystrophy (DMD). 
Involvement of the respiratory muscles leads to progressive hypoventilation and/or 
recurrent atelectasis and pneumonia secondary to decreased cough efficacy. Lung 
volume recruitment (LVR) is a means of stacking breaths to achieve maximal lung 
inflation (MIC), prevent micro-atelectasis, and improve cough efficacy. Although it has 
been recommended by some experts as the “standard of care” for individuals with 
neuromuscular disease, the strategy has not been widely implemented in DMD given the 
lack of clinical trials to date to support its efficacy as well as the additional burden of 
care required in a population already requiring multiple interventions. 
Primary Objective: To determine whether LVR, in addition to conventional treatment, 
is successful in reducing decline from baseline in forced vital capacity (FVC) over 2 
years (percent predicted, measured according to American Thoracic Society standards), 
compared to conventional treatment alone in children with DMD. 
Secondary Objectives: To determine differences between children treated with LVR in 
addition to conventional treatment, compared to those treated with conventional 
treatment alone, in: (1) the number of courses of antibiotics, hospitalizations and 
intensive care admissions for respiratory exacerbations, (2) health-related quality of life, 
and (3) peak cough flow and other pulmonary function tests. 
Methods: We propose a 3-year multi-centre randomized controlled trial involving 
fifteen tertiary care pediatric hospitals across Canada. The study population consists of 
boys aged 6-16 years with DMD and FVC ≥ 30% of predicted. A sample size of 110 
participants will be enrolled. This has been informed by chart review and survey of 
participating centres to be feasible, and will be re-assessed with an ongoing internal pilot 
study. Intervention: Participants will be allocated with a minimization procedure to 
receive conventional treatment (non-invasive ventilation, nutritional supplementation, 
physiotherapy and/or antibiotics, as decided by the treating physician) or conventional 
treatment plus twice daily LVR exercises performed with an inexpensive, portable self-
inflating resuscitation bag containing a one-way valve and a mouthpiece. Data 
Analysis: The primary outcome (change in percent predicted FVC over 2 years) will 
be compared between the two study groups using an analysis of co-variance 
(ANCOVA) that takes into account baseline FVC and minimization factors. 
Importance: Decline in pulmonary function among children with DMD negatively 
affects quality of life and predicts mortality. The relatively simple strategy of LVR has 
the potential to optimize pulmonary function and reduce respiratory exacerbations, 
thereby improving quality of life for individuals with DMD. This study is novel in that it 
is the first randomized controlled trial of LVR. A major strength is that the results will 
give support or refute recommendations regarding inclusion of LVR in the standard of 
care for individuals with DMD worldwide. 
 
 
 

Stacking Exercises Attenuate the Decline in Forced Vital Capacity and Sick Time 
(STEADFAST) 
Katz 
 
Jesse’s Journey 2013 
Protocol Version_ Extension Amendment 3_4 June 2015 
 
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LAY LANGUAGE SUMMARY OF PROJECT   
 
Duchenne Muscular Dystrophy is complicated by weak breathing muscles and lung 
infections. "Lung volume recruitment" is a technique performed using a face mask or 
mouthpiece and a hand-held resuscitation bag to stack breaths, inflate the lungs and help 
clear the airways of secretions by increasing the forcefulness of a cough. We believe this 
will slow down the steady loss of lung function, prevent lung infection, and improve 
quality of life. Our aim is to compare the outcome of a group of individuals with DMD 
treated with standard care to another group that also receives lung volume recruitment. 
If effective, this study will change clinical practice by including twice-daily treatment as 
part of the standard of care for individuals with DMD, in order to improve their lung 
health and quality of life. 
 
 
 
LAY LANGUAGE DESCRIPTION OF PROJECT DISSEMINATION/ 
KNOWLEDGE TRANSFER STRATEGIES    
 
Publication of the results of this trial in a peer-reviewed journal and presentation at 
international conferences will educate inter-professional healthcare teams, patients and 
families about this therapeutic tool. Demonstrating benefits of lung volume recruitment 
on lung function and quality of life will lead to more widespread adoption and support for 
this treatment in DMD patients worldwide. The results can be used to inform care 
recommendations for individuals with DMD and may be incorporated into guidelines for 
respiratory health maintenance in this population. The results of this study may also be 
applicable to the care of individuals with other neuromuscular conditions. 

Stacking Exercises Attenuate the Decline in Forced Vital Capacity and Sick Time 
(STEADFAST) 
Katz 
 
Jesse’s Journey 2013 
Protocol Version_ Extension Amendment 3_4 June 2015 
 
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DETAILED PROJECT PROPOSAL   
 
BACKGROUND DATA  
 
Respiratory failure is the primary cause of morbidity and mortality in children 
with Duchenne Muscular Dystrophy (DMD). In the absence of a definitive treatment for 
the underlying disease, management focuses on supportive measures to slow the decline 
in lung function, prevent respiratory infection and improve quality of life. The goal of 
this study is to determine whether introduction of twice-daily lung volume recruitment 
(LVR), in addition to current standard treatment, reduces the rate of decline in pulmonary 
function and the frequency of respiratory exacerbations in children with DMD, compared 
to the current standard treatment. 
 
REVIEW OF THE LITERATURE  
 
We are aware of only one controlled clinical trial, which compared efficacy of 
mechanical inexsufflation at 1 point in time between individuals with and without bulbar 
involvement with Amyotrophic Lateral Sclerosis (ALS, a neuromuscular condition 
affecting adults).1 A systematic review of airway clearance techniques in ALS concluded 
there was level 2 evidence for the use of mechanical insufflation followed by an assisted 
cough in improving peak cough flow, but only level 4 evidence that long-term use could 
prevent pulmonary infections and hospitalizations.2 There were no systematic reviews on 
either the use of LVR in improving lung function in neuromuscular disease nor any on 
the use of LVR in neuromuscular disease in children. 
 
RATIONALE FOR THE PROJECT  
A. Duchenne Muscular Dystrophy (DMD) is an important health problem  
 
DMD is a progressive neuromuscular disease presenting in childhood, with an 
estimated incidence of 1 in 3600-6000 live male births.3-6 There is no definitive treatment 
for the underlying condition.7,8 Mortality increases substantially in early adulthood, with 
a median life expectancy of 25-35 years.7,9 Respiratory complications are the primary 
cause of morbidity and mortality, as progressive inspiratory and expiratory respiratory 
muscle weakness leads to hypoventilation10-18 and/or recurrent pneumonia19,20 secondary 
to decreased cough efficacy.21,22 Decreased chest wall motion due to weakened 
inspiratory muscles also results in reduced chest wall compliance, with decreased lung 
volumes leading to micro-atelectasis and reduction in elastic properties of lung tissues.23 
Ultimately, 24-hour ventilatory support is required, necessitating continuous caregiver 
support, and significant healthcare costs.24 In Australia, the burden of care for muscular 
dystrophies is estimated to be $435 million per year, or $125,000 per person annually; 
total cost to society due to disability and premature death exceeds $1 billion.25  
B. LVR Techniques are sometimes included in current management strategies:  
Respiratory management strategies currently focus on three interrelated areas: 1) non-
invasive ventilation for nocturnal hypoventilation; 2) lung volume recruitment (LVR)26; 
and 3) airway clearance.21,26-29 LVR is a means of stacking breaths to achieve maximal 
lung insufflation capacity, expanding the chest wall and filling the lungs with air. 
Insufflation may also help to maintain chest wall motion and lung compliance.27  
 
LVR can be delivered with two technologies: manual insufflations and 
mechanical inexsufflation. For manual delivery, the self-inflating resuscitation bag and 

Stacking Exercises Attenuate the Decline in Forced Vital Capacity and Sick Time 
(STEADFAST) 
Katz 
 
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Protocol Version_ Extension Amendment 3_4 June 2015 
 
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patient interface with a 1-way valve (Appendix 1) is readily available, inexpensive ($70), 
lightweight, requires no external power, and is easily portable. This technique has been 
used in adults with neuromuscular disease and described in detail by Dr. McKim 
(http://www.irrd.ca/education).30  For mechanical delivery, the Respironics In-exsufflator 
(http://www.coughassist.com) provides positive pressure breaths, followed by a rapid 
negative pressure to mimic a cough.19,21,31 It is, however, expensive ($4500-6,000), 
cumbersome, requires external power, is less easily portable, and is not covered by any 
Canadian provincial insurance plan. Therefore, we have chosen to study LVR with an 
inexpensive self-inflating bag. 
C. LVR has not been rigorously studied 
 
While LVR has been shown to improve cough efficacy, the effect on slowing the 
progression of restrictive respiratory impairment has not been evaluated in long-term 
studies. Most studies performed to date have incorporated LVR as an integral part of an 
overall approach to care, making it difficult to assess its impact alone on clinical course.14  
Only 3 small studies included children, all of which involved mechanical inexsufflation. 
One case series, which studied mostly adults, demonstrated an improvement in maximum 
insufflation capacity (MIC, the maximum volume of air that can be held in the lungs with 
a closed glottis after breath-stacking), despite a decrease in forced vital capacity (FVC), 
over 0.5 – 24 years of follow-up in 282 patients with neuromuscular disease.32 Integrating 
the mechanical in-exsufflator into an overall plan of care has also been successful in 
some case series in avoiding hospitalization, pneumonias, episodes of respiratory failure 
and tracheostomy.19,33-36 A similar protocol using non-invasive positive pressure 
ventilation (NPPV) and LVR has been used in a prospective cohort study to avoid 
intubation and death in episodes of acute respiratory failure in 79.2% of adults with 
neuromuscular disease.37 It is difficult to determine however, whether the improved 
outcomes in these studies were due to NPPV or the mechanical inexsufflator. 
 
A single cohort study of adults and children using mechanical in-exsufflation 
twice daily (as per self-report) demonstrated improvement in MIC and PCF over time.23 
In a largely pediatric population there has only been 1 retrospective review of long-term 
regular (once a day to every 4 hours) use in 62 individuals with neuromuscular disease 
and impaired cough (age range 3 months to 28.6 years), with a median duration of 13.4 
months.38 6% of participants experienced an improvement in chronic atelectasis and 8% 
noted a reduction in frequency of pneumonias, although the number of acute lower 
respiratory tract infections was too small to permit meaningful comparison with a pre-
treatment period.  
 
Our recently completed retrospective cohort study, published in Archives of 
Physical Medicine and Rehabilitation,39 describes the trajectory of pulmonary function in 
adults with DMD, in whom LVR has been used for up to 2 years. The annual change in 
percent-predicted FVC before introduction of LVR was approximately -4.7 %-predicted 
per year, which is consistent with literature suggesting the rate of decline of pulmonary 
function plateaus in adulthood, with severe disease.40 After LVR introduction, the rate of 
decline decreased to -0.5 %-predicted/year. The difference between the two rates was 4.2 
%-predicted/year (p < 0.001), demonstrating significant benefit of LVR (Appendix 2).  
 
In summary, there are no trials, nor any long-term controlled prospective studies 
evaluating LVR as a treatment for children with DMD, although the existing literature of 

Stacking Exercises Attenuate the Decline in Forced Vital Capacity and Sick Time 
(STEADFAST) 
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Jesse’s Journey 2013 
Protocol Version_ Extension Amendment 3_4 June 2015 
 
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uncontrolled studies suggests that LVR may be beneficial for adults with neuromuscular 
disease.  
D. Current Standards of Care and Questions Remaining 
LVR has been recommended by Bach and Finder as the “standard of care” for 
neuromuscular patients.14,19,29,33,34,41,42 The paucity of long-term clinical studies to 
demonstrate its efficacy has left questions, with several groups worldwide calling for 
further prospective, controlled studies.21,38,43-46 It was listed as a top research priority in 
recent British Thoracic Society Guidelines on “Respiratory Management of Children with 
Neuromuscular Weakness”.47 Our recent Survey of Respiratory Management of 
Neuromuscular Disease revealed that LVR has been adopted for management of 
intercurrent infections by Pediatric Respirologists and Neuromuscular Specialists at many 
Canadian centres (Appendix 3). No centres are routinely prescribing regular LVR use. It 
is used at only 3 centres and in less than one third of their patients, during periods of 
clinical stability.48  
Clinical equipoise therefore currently exists regarding the use of regular LVR in 
children with neuromuscular disease. Given the additional burden of this therapy on 
children and caregivers, it requires closer evaluation before it can be recommended on a 
routine basis. 
 
HYPOTHESIS/RESEARCH QUESTIONS 
We propose a novel single-blind randomized controlled trial (RCT) of LVR in DMD, 
allowing evaluation of the impact of its implementation in clinical care. 
Primary Question: Will adding twice-daily LVR to the standard treatment received by 
children with DMD reduce the decline in FVC %-predicted by at least 30% over 2 years?  
Secondary Questions: Will adding LVR to standard treatment received by children with 
DMD:  
1. increase time to FVC decline of 10% of predicted from baseline? 
2. reduce the number of outpatient antibiotic treatment courses, hospitalizations and/or 
admissions to intensive care (ICU) for respiratory exacerbations? 
3. improve the health-related quality of life (HRQL) of children with DMD? 
4. affect the decline of unassisted peak cough flow (PCF), maximum insufflation 
capacity (MIC), maximal inspiratory and expiratory pressures (MIP, MEP)? 
 
SPECIFIC OBJECTIVES 
1. To determine the impact of twice-daily LVR on relative decline in FVC %-
predicted and other functional parameters (PCF, MIC, MIP, MEP) over 2 years 
2. To determine the impact of twice-daily LVR on antibiotic courses, 
hospitalizations and ICU days, as well as quality of life, over 2 years 
3. To inform care guidelines on LVR therapy for individuals with DMD 
 
PROJECT DESIGN AND RESEARCH METHODOLOGY 
 
1. PROPOSED TRIAL DESIGN & INTERVENTIONS 
 
This will be a multi-centre single-blind parallel RCT. The study will involve 10 
tertiary care Pediatric hospitals across Canada (Appendix 4) and will run for 5 years 
(August 2013- August 2018). The coordinating centre will be the Children’s Hospital of 
Eastern Ontario (CHEO) in Ottawa, Ontario. Recruitment will take place from August 
2013- 30 April 2016.  Participants will be randomized 1:1 to conventional treatment 

Stacking Exercises Attenuate the Decline in Forced Vital Capacity and Sick Time 
(STEADFAST) 
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Jesse’s Journey 2013 
Protocol Version_ Extension Amendment 3_4 June 2015 
 
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alone, or conventional treatment plus LVR. The intervention will occur for 24 months 
and participants will be followed up in clinic at Baseline, 6, 12, 18 and 24 months. 
(Appendix 5- Flow Diagram and Activities).  
 
Treatment Groups 
Conventional Treatment will be coordinated by the treating physician. This may 
include: a. Physiotherapy, consisting of percussion, active cycle of breathing and/or 
postural drainage; b. Nutritional support, consisting of oral or tube-fed dietary 
supplements; c. Antibiotics (oral or intravenous), if there is evidence of respiratory 
infection; d. Non-invasive positive pressure ventilation, if there is evidence of nocturnal 
hypoventilation or sleep-disordered breathing; e. Systemic steroids.e) LVR therapy 
during acute respiratory exacerbations only 
Intervention Treatment: Conventional treatment plus the use of LVR twice per day. 
 
Interventional Procedures 
Caregivers of those who are randomized to the interventional arm will receive 
equipment (free of charge) and training in provision of LVR. Technique (Appendix 6) 
will be reviewed by a respiratory therapist or physiotherapist trained to use this 
equipment, prior to initiation of home use of the device. Positive pressure, via a 
mouthpiece, will be applied using a resuscitation bag containing a one-way valve. 
Insufflation volume will be determined by clinical evaluation, consisting of visual 
inspection of chest wall excursion38 and patient comfort. The initial positive pressure 
setting will be titrated individually as tolerated, to a maximum of 40 cmH2O.42,46 
Pressures will be measured with a manometer and re-evaluated at each follow-up clinic 
visit. 
Positive pressure breaths will be delivered in coordination with the subject’s own 
respiration over 2-3 seconds. 3-5 breaths will be delivered in order to achieve MIC, 
followed by a cough while the subject is at MIC, for a total of 3-5 cycles, as tolerated. 
Airway suctioning will be performed at the end of each cycle as needed. Twice daily 
LVR will be performed prior to meals or at least 2 hours after meals to eliminate risk of 
aspiration of abdominal contents.  
 
Adherence with therapy will be monitored via a data-logging device in-line with 
the resuscitation bag that records number of compressions of the resuscitation bag along 
with the time and date (Appendix 7). Data from the device memory will be uploaded by 
the research assistant at each study visit and sent to the central coordinating centre 
(CHEO). Since the minimum frequency of LVR use to achieve clinical benefit is 
unknown, for study purposes, adherence with the study intervention is defined as a 
participant using LVR for at least 50% of sessions during each year of the study, based 
on a consensus of investigators (Drs. Katz, Kovesi, Mah, McKim, and MacLusky).  
Rescue Treatment: During acute respiratory exacerbations, subjects may use 
assisted cough techniques, including LVR with or without an abdominal thrust and/or 
mechanical in-exsufflator, even if they are in the control group, if deemed appropriate by 
the treating physician. Brief use of such treatment is unlikely to affect the primary 
outcome, and therefore is not a criterion for withdrawal from the study. Rescue treatment 
is typically initiated and carried out by clinical care teams during hospitalizations for 
respiratory exacerbations (Appendix 8). 

Stacking Exercises Attenuate the Decline in Forced Vital Capacity and Sick Time 
(STEADFAST) 
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Jesse’s Journey 2013 
Protocol Version_ Extension Amendment 3_4 June 2015 
 
9
 
 
2.  ALLOCATION OF PARTICIPANTS TO TRIAL GROUPS  
 
Along with the study site, use of systemic steroids,49 baseline FVC (%-
predicted),40 degree of scoliosis,18 age,40 and ambulatory status were considered as 
important prognostic indicators in the design of this study, each believed to influence the 
primary outcome, FVC (Justification in Appendix 9). Although stratified block 
randomization is commonly used to ensure balanced prognostic factors in larger trials, 
the method of minimization is optimal for the number of prognostic factors 50,51 and study 
size. The method of “minimization” 52 is described in the CONSORT statement as a 
methodologically equivalent alternative to randomization. 53 Patients will be allocated to 
the intervention or control group (1:1 ratio) using a centralized computer algorithm 
designed by the study statistician and maintained by the Data Management Group of the 
Ottawa Hospital Research Institute. 
 
  
3 METHODS FOR PREVENTING BIAS 
A. Concealment of allocation. Centralized allocation and random elements in the 
minimization will ensure participating centres cannot predict the allocation sequence.  
B. Masking of intervention from outcome assessor. The study will be single-blinded, 
where the pulmonary function assessors will not know the participants’ group 
assignment. Furthermore, the outcomes used are objective tests with defined performance 
criteria for acceptability54. 
 
4.  INCLUSION/EXCLUSION CRITERIA 
Inclusion Criteria 
 Age 6-16 years – This age range was selected as there are accepted normative 
pulmonary function data 55 and children 6 years of age and older are generally able to 
reliably perform pulmonary function tests. Children are followed in participating 
centres until they reach 18 years of age (allowing two years of follow-up).  
 Clinical phenotypic features consistent with DMD and confirmed by either: (1) 
Muscle biopsy showing complete dystrophin deficiency; (2) Genetic test positive for 
deletion or duplication in the dystrophin gene resulting in an 'out-of-frame' mutation; 
or (3) Dystrophin gene sequencing showing a mutation associated with DMD.5 
 FVC ≥ 30% predicted - This range of pulmonary function was selected to exclude 
those with severe restrictive respiratory impairment, who are less likely to be able to 
reliably perform pulmonary function testing over a two year period.  Ability to 
perform a single acceptable flow-volume curve meeting criteria for test acceptability 
as per American Thoracic Society standards is required. 54  
 A caregiver willing to provide the therapy 
 Fluency in English or French 
Exclusion Criteria 
 Unable to perform pulmonary function tests and/or LVR manoeuvre  
 Presence of an endotracheal or tracheostomy tube 
 Already using LVR and/or the Respironics in-exsufflator between and during 
respiratory infections 
 Known susceptibility to pneumothorax or pneumomediastinum  
 Uncontrolled asthma or other obstructive lung disease 

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 Symptomatic cardiomyopathy ( ejection fraction less than 50% ) 
 
 
5. FREQUENCY AND DURATION OF FOLLOW-UP  
Participants will return to clinic 6 month after study initiation and then every 6 
months (± 2 months) for follow-up, over a 2-year period from time of enrolment. At each 
visit, pulmonary function testing will be performed (including FVC, MIC, MIP, MEP, 
PCF, maximum and average pressure achieved during LVR measured, and technique 
reviewed). Participants will meet with the study assistant by telephone every 3 months (or 
in clinic), to document courses of oral antibiotics and hospital admissions. LVR use will 
be recorded using a portable data-logger in-line with the LVR set-up.  
 
6. PRIMARY AND SECONDARY OUTCOME MEASURES 
Primary 
Relative decline in FVC (%-predicted) over 2 years, measured according to American 
Thoracic Society (ATS) standards, using the Stanojevic normative equations.55 Relative 
decline in FVC (%-predicted) was chosen as the primary outcome as it is a strong 
predictor of subsequent respiratory failure and mortality.56,40  Although survival is not a 
realistic endpoint for this trial, given expected mortality is less than 5%9 for the pediatric 
age group, FVC decline is an appropriate clinical laboratory measure and valid surrogate 
endpoint to use for this trial. 
Secondary 
a. Time to FVC decline of 10% of predicted. 
b. Total number and duration of outpatient oral antibiotic courses, hospital and ICU 
admissions for respiratory exacerbations over 2 years.  
c. Change in HRQL over 2 years (PedsQL 4.0, Pediatric Quality of Life Inventory and 
PedsQL DMD 3.0), biannually  
d. Change in unassisted PCF, MIC, MIP, MEP, as well as MIC and PCF with LVR  
Exploratory  
e. Maximal and average pressure achieved with LVR (cmH2O) 
f. Respiratory symptoms, as assessed every 3 months by phone and personnel interview 
at clinic visits (Appendix 10_A self-report usage diary (Appendix 12)will be given to the 
participant to record daily activities to help with recall at the telephone follow ups 
(Appendix 10) 
g. Satisfaction with LVR, as assessed every 3 months by phone (Appendix 11) 
 
Spirometry, including FVC, will be performed according to ATS standards.54 The 
Stanojevic normative equations will be used to calculate %-predicted values for FVC and 
FEV1.55 Measurements of MIC, MIP, MEP and PCF will be performed according to 
established protocols. 57-61 Maximal and average pressure achieved with LVR (cmH2O) 
will be measured with a manometer at the time of each pulmonary function test.  Adverse 
events will also be recorded (Appendix 12). Data collection forms are found in Appendix 
13.  
 
 
7.  SAMPLE SIZE AND JUSTIFICATION  
The consensus from a national survey of Respirologists and Neuromuscular 
Specialists treating children with neuromuscular disease was that a 30% relative 
reduction in the average decline in FVC percent predicted would represent the minimal 

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clinically important difference (MCID) that would be important to detect in this trial. 48 
This magnitude of pulmonary function change has been deemed clinically important in 
trials of treatment to decrease the decline in lung function in Cystic Fibrosis, another 
progressive childhood respiratory disease, 62 and should be achievable, based on pilot 
data in adults with DMD that demonstrated an 89% relative reduction in the rate of 
decline of FVC after LVR was introduced (Appendix 2).  
 
The following assumptions were used: i) a decline of 12% predicted in FVC over 
2 years in the control group (based on an estimate of decline in FVC of 6% predicted per 
year, being more conservative than the published -8.0% per year decline (range 2-39%) 
in boys ≥ 10 years old with DMD;56,63 ii) an absolute MCID of 3.6% FVC 
(corresponding to a relative 30% MCID); iii) an estimated standard deviation (SD) of 
5.5% in the change of FVC from baseline (the SD of the annual change of FVC was 
reported to be 4.1%).63 With a 2-year follow-up, the SD of the change of FVC from 
baseline is likely to be greater than 4.1%, and is assumed to be 5.5%; iv) two-sided test; 
v) a power of 80% and a type I error of 5%. With these assumptions, the total sample size 
needed is 76 participants. We believe the non-adherence rate in the treatment arm will be 
10%.  We also expect very few individuals to cross-over from control to intervention, 
barring a few cases of rescue therapy.  We have therefore conservatively estimated this at 
2%.  Accounting for noncompliance, cross-overs, and 10% losses to follow-up, the total 
sample size will be 110.64,65  
 
 
8. PLANNED RECRUITMENT RATE 
Participants will be recruited from established neuromuscular clinics at the participating 
centres (chart review has revealed 254 individuals who are eligible for this study, 
Appendix 4). We conservatively anticipate 60% of eligible patients will agree to 
participate in the study.  
 
 
9. ADHERENCE 
Adherence to therapy will be monitored using a device in line with the resuscitation 
bag (Appendix 7), as well as self-report usage diary, (Appendix 12). Given the 
progressive and eventually fatal nature of the disease, this population is generally highly 
motivated to pursue treatments. We anticipate a 90% adherence rate, seen in other studies 
in this and similar populations when non-invasive ventilation was implemented for up to 
4 – 7 years.66,67  
 
 
10.  ANALYSIS PLAN 
Intention to treat and per protocol analyses 
The primary analysis will follow the intention-to-treat principle. A per-protocol 
secondary analysis will also be performed. Adherence in the intervention group will be 
defined as using LVR for a minimum of 50% of sessions during each year of the study, 
based on a consensus of experts.68  
Primary analysis: An analysis of covariance will be conducted for FVC %-predicted at 
2-years follow-up, adjusting for baseline FVC %-predicted, treatment group, centre, use 
of systemic steroids, presence of scoliosis, age, and ambulatory status. A 2-sided p-value 
less than 0.05 for treatment group will indicate a statistically significant group effect.  
Secondary analyses:  To account for differences in adherence, the primary analysis will 
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The slope of decline in FVC (measured every 6 months) will be plotted for each study 
group and differences between groups will be assessed using linear mixed effects models 
for repeated measures, adjusting for patient covariates such as baseline FVC %-predicted, 
treatment group, centre, use of systemic steroids, presence of scoliosis, age, and 
ambulatory status.   In addition, in each study group, the time for each participant’s FVC 
%-predicted to decline by an absolute 10% from baseline value will be displayed using 
Kaplan-Meier curves, and compared between the study groups using a log rank test.  Cox 
proportional hazards models will also be used to adjust survival time for the important 
prognostic risk factors listed above.  
Poisson regression models, allowing for possible over-dispersion, will be fit to assess 
the differences in a) the number of courses of oral antibiotics for respiratory infections; b) 
the number of hospitalizations for respiratory exacerbations; c) the number of admissions 
to the intensive care unit; d) the total number of days requiring intubation and mechanical 
ventilation over the study period and, e) PedsQL scores.  
A comparison will be made of frequencies of the most common adverse events 
between the two study groups using chi-square or Fisher’s exact test. 
Sub-group analysis will also be performed to compare the primary outcome between 
those who are adherent with LVR but experience no improvement in MIC after LVR (i.e. 
MIC is equal to FVC) and those who experience an increase in MIC after LVR (i.e. MIC 
is greater than FVC). Given the exploratory nature of this subgroup analysis, we will 
interpret the results cautiously.  
 
  
PILOT STUDIES 
1. National Practice Survey: We recently published 48 a Canadian survey of Pediatric 
Respirologists’ and Neuromuscular Specialists’ respiratory management of individuals 
with neuromuscular disease. This assisted in informing the feasibility of the study and 
confirmed that while no centres are routinely prescribing LVR for use between 
respiratory exacerbations, there is strong support for research into LVR therapy, with our 
proposed intervention selected as most important by respondents (Appendix 3). 
2. Evaluation of Adherence Monitoring Device: Drs. McKim and Katz have completed 
a study evaluating the performance of the in-line data-logging device to monitor 
adherence to LVR, compared to nursing report, on in-patients with neuromuscular 
disease. We demonstrated substantial correlation in the number of LVR cycles/session 
between nurses and the device (Wilcoxon signed rank test, p=0.531, Spearman 
correlation co-efficient 0.76, Intra-class correlation coefficient 0.59 - Appendix 7). 
3. Retrospective Cohort Study of Adults with DMD Using LVR: Drs. McKim and 
Katz have published a manuscript in Archives of Physical Medicine and Rehabilitation, 
describing the trajectory of pulmonary function in adults with Duchenne Muscular 
Dystrophy, in whom LVR has been used for up to 2 years.39 The difference between the 
two rates was 4.2 %-predicted/year, demonstrating significant benefit of LVR, with an 
89% relative reduction in the rate of decline of FVC per year (p < 0.001) (Appendix 2) 
 
 
 
 

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TIMELINE/MILESTONES 
  
 
STEERING COMMITTEE AND DATA SAFETY MONITORING BOARD  
The study Executive Committee will consist of Dr. Katz (PI), as well as Dr. 
MacLusky, Pediatric Respirologist and Dr. Barrowman, Statistician. Drs. Katz and 
MacLusky have collaborated previously on a multi-centre cohort study evaluating the 
impact of non-invasive ventilation in childhood neuromuscular disease.69-72Dr. Katz is 
currently running a CIHR-funded multi-centre prospective cohort study evaluating the 
impact of non-invasive ventilation in obese adolescents. She has formal research training 
with a Master’s of Science and has completed the Royal College Clinician Investigator 
Program at the University of Toronto.  
The Team will be strengthened by Drs. Momoli (Epidemiologist),  Dr. Aaron and Ms. 
Hoey, a senior research coordinator with the CHEO CRU, who have successfully run 
CIHR-funded multi-centre studies.  Drs. McKim and Kovesi have pioneered the 
introduction of LVR techniques in Canada. Dr. Mah is a Pediatric Neurologist involved 
in DMD research, who leads the Canadian Pediatric Neuromuscular Group, who support 
this project (Appendix 15).  A Data Safety Monitoring Committee of experienced 
clinicians and clinical trialists not involved with the study will examine data annually and 
advise the Steering Committee. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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DSMB 
Committee Membership  
 
Committee 
Membership 
Safety  Monitoring 
Committee* 
Dr. J. Reisman, Dr. Lee Burkholder,, Dr. Andrea 
Benedetti and Dr. Robert Dales 
Executive Committee 
Dr. Sherri Katz, Dr. Ian MacLusky and Dr. Nick 
Barrowman 
Steering Committee 
Co-applicants and Collaborators  
Study Consultants 
Dr. S. Aaron 
* Safety Monitoring Committee will be experienced clinicians and trialists, who will not 
be involved in the day-to-day running of the study. 
 
Committee Roles 
 
 
 
 
 
 
 
 
 
 
  Safety Issues 
 
 
 
   
   
Protocol Matters 
 
 
 
 
 
 
   Clinical & Practical Issues 
 
 
 
 
The participating Principal Collaborators and their clinical centre staff are responsible for the 
conduct of the study at their own institutions. They will interact with the Executive Committee on 
clinical and practical issues related to the trial. Additional collaborators may be added at each 
centre at the discretion of the principal investigator.  There will be a research nurse coordinator 
(part-time or full-time) specifically assigned to the study.   
 
The Steering committee will include the Executive Committee, as well as co-applicants and 
collaborators. It will have responsibility for the design, execution, analysis and publication of 
Trial results. It will convene monthly by conference call and monthly study bulletins will be sent 
to each site.  
 
A Data Safety Monitoring Committee of experienced clinicians and clinical trialists not involved 
with the study will examine data annually and advise the Steering Committee on continuation or 
early termination of the trial, based on clear guidelines defined at the first meeting. 
Executive 
Committee 
Data Safety 
Monitoring 
Study Consultants 
Steering Committee 
Clinical Centers 

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ACRONYMS 
 
%-predicted – percent predicted 
ALS – Amyotrophic Lateral Sclerosis 
ATS – American Thoracic Society 
CHEO – Children’s Hospital of Eastern Ontario 
CIHR – Canadian Institutes of Health Research 
cmH2O – centimeters of water 
CRU – Clinical Research Unit 
DMD – Duchenne Muscular Dystrophy 
FVC – forced vital capacity (percent-predicted) 
HRQL – health-related quality of life 
ICU – intensive care unit 
LVR – lung volume recruitment 
MCID – minimum clinically important difference 
MEP – maximum expiratory pressure (cmH2O) 
MIC – maximum insufflation capacity (litres) 
MIP – maximum inspiratory pressure (cmH2O) 
NPPV – noninvasive positive pressure ventilation 
PCF – peak cough flow (litres/minute) 
PedsQL – Pediatric Quality of Life Inventory 
RCT – randomized controlled trial 
SD – standard deviation 
 
 
 
 
 
 
 
 
 
 
 

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ANTICIPATED IMPACT/RELEVANCE TO DUCHENNE MUSCULAR 
DYSTROPHY 
 
 
In Duchenne Muscular Dystrophy (DMD), a neuromuscular disease for which there is 
no cure, progressive respiratory muscle weakness results in decline in pulmonary 
function, leading to impaired quality of life, enormous costs to families and the health 
care system, and respiratory failure, which is the cause of death in over 85% of patients 
with this condition. Our proposed study of Lung Volume Recruitment (LVR) therapy 
in children and youth with Duchenne Muscular Dystrophy is relevant to Jesse’s Journey 
Foundation, because the intervention we propose to study has the potential to slow the 
decline in pulmonary function in this condition, and because the intervention is easily 
performed, inexpensive, and safe. In small studies, it has been shown to considerably 
enhance lung volume and cough capacity in adults with DMD. This simple, non-
pharmacologic treatment, consisting of stacking breaths to inflate the lungs, has 
potential to preserve lung function by preventing micro-atelectasis and reducing 
contractures of the intercostal muscles, preventing restriction of the thoracic cage. It also 
enhances cough efficacy and airway clearance, which may prevent atelectasis and 
pneumonia. By preserving lung function, LVR has the potential to decrease mortality 
and improve quality of life for individuals with DMD. The findings from this study 
can be directly translated into clinical practice, within 3 years, at the conclusion of the 
project.  
 
There are no long-term controlled prospective studies evaluating LVR as a treatment in 
neuromuscular disease. As a result, adoption of LVR has been limited, with several 
groups worldwide calling for further prospective, controlled studies. Our recent 
Canadian survey revealed that LVR is not routinely prescribed for regular use at any 
Canadian Pediatric Centre. The potential of regular LVR to maintain lung function (a 
measure directly related to respiratory complications and mortality) and alter the clinical 
practice of respiratory health maintenance in this population, must be investigated in 
order that this simple therapy becomes widely available to those who will benefit. We 
therefore believe that a randomized controlled trial is critical to establish the role of 
LVR in the care of DMD patients to assist in recommendations of standards of care 
for this population both in Canada and worldwide. Results of this study will also have 
application in the management of other neuromuscular conditions, making this a study 
of great clinical relevance with direct impact on patient care.  
 
 
 
 
 
 

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in-exsufflator in pediatric patients with neuromuscular disease and impaired 
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2011. Forthcoming. 
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Coates AL, Pan H, Rosenthal M, Corey M, Lebecque P, Cole TJ. Reference 
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over time as a prognostic marker in patients with Duchenne muscular dystrophy. 
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 57.  Kang SW, Kang YS, Sohn HS, Park JH, Moon JH. Respiratory muscle strength 
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 58.  Kang SW, Shin JC, Park CI, Moon JH, Rha DW, Cho DH. Relationship between 
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 59.  Sancho J, Servera E, Diaz J, Marin J. Predictors of ineffective cough during a 
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flows in neuromuscular disease. Am J Phys Med Rehabil 2000 May;79(3):222-7. 
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Dubrovsky A, De Vito EL. Peak flow and peak cough flow in the evaluation of 
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neuromuscular disease. American Journal of Physical Medicine & Rehabilitation 
2002 Jul;81(7):506-11. 
 62.  Hodson ME, McKenzie S, Harms HK, Koch C, Mastella G, Navarro J, Strandvik 
B. Dornase alfa in the treatment of cystic fibrosis in Europe: a report from the 
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fusion for scoliosis in duchenne muscular dystrophy diminishes the rate of 
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 64.  Wittes J. Sample size calculations for randomized controlled trials. Epidemiol 
Rev 2002;24(1):39-53. 
 
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Hardison WG, Shaw LW, Thistle JL, Vlahcevic ZR. Design and methodological 
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DE, Brouillette RT, Trang HT, Brooks LJ. Use of nasal continuous positive 
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Pediatrics 1995 Jul;127(1):88-94. 
 67.  Janssens JP, Derivaz S, Breitenstein E, De MB, Fitting JW, Chevrolet JC, Rochat 
T. Changing patterns in long-term noninvasive ventilation: a 7-year prospective 
study in the Geneva Lake area. Chest 2003 Jan;123(1):67-79. 
 68.  McKim D, MacLusky IB, Kovesi T, Spier S, Mah JK, Katz S [Letter to 
Anonymous, 2010]. 
 69.  Katz SL, Gaboury I, Keilty-Lau K, Banwell B, Vajsar J, MacLusky IB. Clinical 
Predictors of Nocturnal Hypoventilation in Children with Static or Progressive 
Neuromuscular Disease. American Journal of Respiratory and Critical Care 
Medicine 2008;177(Abstracts):A708. 
 70.  Katz SL, Gaboury I, Anderson P, Collins D, Keilty-Lau K, Nicholas D, Boyd J, 
Banwell B, Vajsar J. Natural history of psychological function and quality of life 
in children with neuromuscular disease. 12th International Conference on Home 
Mechanical Ventilation, Barcelona 2009. 
 71.  Katz SL, Gaboury I, Anderson P, Collins D, Keilty-Lau K, Nicholas D, Boyd J, 
Banwell B, Vajsar J. Impact of non-invasive ventilation on psychological 
function, quality of life and pulmonary function in children with neuromuscular 
disease and nocturnal hypoventilation. 5th Annual Conference on Pediatric Sleep 
Medicine, Denver, Colorado 2009. 

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 72.  Katz SL, Gaboury I, Keilty K, Banwell B, Vajsar J, Anderson P, Ni A, Maclusky 
I. Nocturnal hypoventilation: predictors and outcomes in childhood progressive 
neuromuscular disease. Arch Dis Child 2010 Dec;95(12):998-1003. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDICES 
 
Appendix 1- LVR SET-UP WITH DATA LOGGER 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 2. LVR PILOT DATA  
 
McKim DA, Katz SL, Barrowman N, Ni A, Leblanc C. Lung Volume Recruitment Slows 
Pulmonary Function Decline in Duchenne Muscular Dystrophy. Arch Phys Med Rehabil 
2012 Mar;93(7):1117-22. (Published on-line ahead of print release). 
This retrospective cohort study was conducted by Drs. McKim and Katz, evaluating the 
impact on the rate of pulmonary function decline, of the introduction of twice daily LVR 
in 20 adult patients (mean age 19.6 years, SD 2.4) with Duchenne Muscular Dystrophy, 
over a minimum two year period before and after introduction of LVR. The median 
duration of follow-up post LVR initiation was 26 months (min 7, max 127). 
 
-100
-50
0
50
100
10
20
30
40
50
60
70
FVC % predicted over time
Month since LVR
FVC % predicted
 
 
Trajectory of FVC (percent-predicted) over time, before and after LVR initiation 
The thin colored lines represent slopes from individual patients. The two thick black lines 
are the fitted slopes before and after LVR initiation, estimated from a linear regression 
model with an interaction term to account for the introduction of LVR. The fitted slope 
prior to LVR initiation was -4.7percent-predicted per year (95% CI: -5.3, 4.2). The fitted 
slope after LVR initiation was -0.5 percent-predicted per year (95% CI: -0.9, -0.1).  The 
difference in the rate of decline of FVC was 4.2 percent-predicted per year, which was 
statistically significant (p<0.001). 
 
 

Stacking Exercises Attenuate the Decline in Forced Vital Capacity and Sick Time 
(STEADFAST) 
Katz 
 
Jesse’s Journey 2013 
Protocol Version_ Extension Amendment 3_4 June 2015 
 
26
APPENDIX 3. SURVEY DATA 
 
Katz SL, McKim D, Hoey L, Barrowman N, Kherani T, Kovesi T, Maclusky I, Mah JK. 
Respiratory management strategies for Duchenne muscular dystrophy: practice variation 
amongst canadian sub-specialists. Pediatr Pulmonol 2013 Jan;48(1):59-66. 
 
The survey was sent to all 56 practicing Pediatric Respirologists in Canada and to all 24 
members of the Pediatric Neuromuscular Interest Group (PNIG) comprised of Pediatric 
Neurologists and Physiatrists. Responses were received from 38 Pediatric Respirologists 
(66%) and 17 Pediatric Neuromuscular Specialists (66%). Of 38 Respirologists, 33 see 
DMD patients under the age of 18. Of these 33, only 6 (18%), practicing at 3 
centres, reported using LVR in their patients at least twice daily during clinical 
stability. On average, these Respirologists reported using LVR on 33% of their patients. 
Of 17 Neuromuscular Specialists, all of whom see DMD patients under the age of 18, 
only 2 (12%), practicing at a single centre, reported using LVR in their patients at least 
twice daily during clinical stability. On average, these Neuromuscular 
Specialists reported using LVR on 50% of their patients.   
  
Study participants were told that a study was being planned to evaluate a 
respiratory treatment for patients with DMD. When asked what the intervention should 
be, the majority of Respirologists (61%) indicated manual LVR between respiratory 
exacerbations. When asked what outcome they would consider most clinically important, 
47% indicated change in FVC decline (% predicted) and 37% indicated quality of life. 
Among Neuromuscular Specialists, the majority (64%) indicated that the intervention 
should be manual LVR between respiratory exacerbations. When asked what outcome 
they would consider most clinically important, 25% indicated change in FVC decline (% 
predicted) and 67% indicated quality of life. While our main focus is on the physiologic 
benefit of LVR, because of the interest in quality of life as an outcome, it has been 
included as a secondary outcome for the proposed study.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Stacking Exercises Attenuate the Decline in Forced Vital Capacity and Sick Time 
(STEADFAST) 
Katz 
 
Jesse’s Journey 2013 
Protocol Version_ Extension Amendment 3_4 June 2015 
 
27
APPENDIX 4. List of Study Sites & Letters of Support 
 
Centre 
number 
Centre 
Investigator 
Centre  Location 
# Eligible Patients 
1 
Children’s Hospital of 
Eastern Ontario  
Dr. Sherri Katz 
Dr. Ian MacLusky 
Dr. Tom Kovesi 
Ottawa, Ontario 
10 
2 
Alberta Children's 
Hospital 
Dr. Jean Mah 
Dr. Mark Anselmo 
Calgary, Alberta 
20 
3 
BC Children’s 
Hospital 
Dr. Michael Seear  
Vancouver, British 
Columbia 
26 
7 
Holland Bloorview 
Kids Rehabilitation 
Hospital 
Dr. Laura McAdam 
Toronto, Ontario 
53 
8 
Hôpital Ste. Justine 
Dr. Thanh-Diem 
Nguyen 
Montreal, Quebec 
26 
10 
London Health 
Sciences 
Dr. Craig Campbell 
London, Ontario 
20 
11 
McMaster University 
Dr Mark Tarnopolsky 
Hamilton, Ontario 
30 
12 
Montreal Children’s 
Hospital 
Dr. David Zielinski 
Montreal, Quebec 
6 
13 
SickKids Hospital 
Dr. Reshma Amin 
Toronto, Ontario 
5 
14 
Stollery Children’s 
Hospital 
Dr. Carina Majaesic 
Edmonton, Alberta 15 
 

Stacking Exercises Attenuate the Decline in Forced Vital Capacity and Sick Time 
(STEADFAST) 
Katz 
 
Jesse’s Journey 2013 
Protocol Version_ Extension Amendment 3_4 June 2015 
 
28
APPENDIX 5: STUDY FLOW DIAGRAM & STUDY ACTIVITIES 
 
Study Flow  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Potentially eligible Child identified by Physician, based 
on neuromuscular disease and pulmonary function 
Research Assistant meets with parents and child 
for consent  
Child is randomized to Conventional therapy or 
Conventional therapy plus lung volume 
recruitment exercises 
Note is written in child’s chart regarding consent 
process and randomization 
Consent signed 
Conventional therapy plus lung volume 
recruitment exercises  
- Baseline questionnaire  
- Baseline  PFT testing 
- Lung volume recruitment exercises 
  training & measurement of maximal 
pressure achieved at participating 
sites only 
Conventional therapy 
- Baseline questionnaire  
- Baseline  PFT Testing 
- Lung volume recruitment 
exercises training & measurement 
of maximal pressure achieved at 
participating sites only 
 
Letter of information sent or given to parent and child. If 
interested in participating in the study they are asked to contact 
RA or identify their interest to clinic nurse 
Interested  - Set up appointment for 
consent  
Not Interested 
No further contact 
Confirm child is eligible for study based on results of Baseline FVC 

Stacking Exercises Attenuate the Decline in Forced Vital Capacity and Sick Time 
(STEADFAST) 
Katz 
 
Jesse’s Journey 2013 
Protocol Version_ Extension Amendment 3_4 June 2015 
 
29
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Clinic Visit 
Participants will be seen in clinic at  
 Baseline, 6, 12, 18 and 24 months  
At clinic visits: 
Conventional therapy plus lung 
volume recruitment exercises 
 
- 
pulmonary function testing  
(including FVC, MIC, MIP, 
MEP and PCF) 
- 
pressure measurements 
documented during LVR  (at 
participating sites only) 
- 
LVR technique reviewed 
- 
Upload data from data-logger 
- 
Review of AE’s and 
Medications 
- 
QOL Questionnaire (baseline 
and 6 months) 
At clinic visits: 
Conventional therapy 
 
- 
pulmonary function testing  
(including FVC, MIC, MIP, MEP 
and PCF) 
- 
pressure measurements 
documented during LVR(at 
participating sites only)  
 
- 
Review of AE’s and Medications 
- 
QOL Questionnaire (baseline and 6 
months) 
Telephone follow-up at months 3, 9, 15 and 21 
months 

Stacking Exercises Attenuate the Decline in Forced Vital Capacity and Sick Time 
(STEADFAST) 
Katz 
 
Jesse’s Journey 2013 
Protocol Version_ Extension Amendment 3_4 June 2015 
 
30
Study Activities 
* only for those randomized to Conventional Therapy plus LVR 
Tests  
 
BaseLine 
Clinic Visit 
3 Month 
Telephone 
Visit 
6 Month  
Clinic Visit 
9  Month 
Telephone 
Visit  
12 Month  
Clinic Visit 
 
15 Month 
Telephone 
Visit  
18 Month  
Clinic Visit 
 
21  Month 
Telephone 
Visit  
24  Month  
Clinic Visit 
 
 
Medical history 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
NPPV usage history 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
Vital signs 
Height, weight, HR, 
BP, RR 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
Pulmonary function 
tests 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
Training for LVR 
technique or Review of 
technique 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Max & average 
pressure 
measurement 
during  LVR 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
Download data from 
data-logger 
 
 
√* 
 
√* 
 
√* 
 
√* 
 
LVR Satisfaction 
 
 
√* 
 
√* 
 
√* 
 
√* 
 
 
Peds QL 
Psychological 
Questionnaires 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
Review Hospital 
admissions 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Review adverse 
events and 
Medications 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 Respiratory Symptom 
Questionnaire 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 

 
Protocol Version_ Extension Amendment 3, 4 June 2015 
 
31
 
APPENDIX 6. LUNG VOLUME RECRUITMENT TECHNIQUE FOR THERAPISTS 
 
Definitions 
LVR 
Lung Volume Recruitment refers to breath stacking techniques, which promote maximum insufflation capacity.  
This includes the use of a self-inflating resuscitator bag with appropriate one-way valve and   a mouthpiece.  
NEVER use a self-inflating resuscitator bag with one-way valves in place on an intubated patient to perform 
LVR. 
 
MIC 
Maximum Insufflation Capacity (MIC) measurement (Litres) is the maximum volume of air that can be stacked 
within a patient’s lungs beyond spontaneous vital capacity. 
MIC is attained when the patient takes a deep breath, holds his breath and then breath stacking is applied using 
a LVR resuscitator bag.   
 
Criteria 
Patient must be alert, cooperative with respiratory manoeuvres and able to communicate 
 
Absolute Contraindications 
Presence of hemoptysis, untreated or recent pneumothorax, nausea, asthma and recent lobectomy 
Increased ICP 
Impaired Consciousness 
DO NOT perform LVR with resuscitation bag if endotracheal tube or tracheostomy tube is in place 
 
Relative Contraindications 
Therapy following meals 
History of Pneumothorax 
Pleural Effusion 
Cardiac Instability  
Patients with long standing thoracic cage restriction may have severely reduced thoracic compliance and will 
require slow incremental insufflations during initial LVR period. 
Bullous emphysema or risk of pneumothorax or pneumomediastinum 
 
Equipment 
Self Inflating Resuscitation Bag, clearly identified NOT for CPR 
50-100 cc corrugated tubing 
One-way valve closest to bag 
One-way valve with inner silicone piece removed, but inner screen intact, positioned closest to patient (prevents 
aspiration in case silicone valve becomes dislodged!) 
mouthpiece  
nose clip  
 
Procedure for Therapist to Teach 
Assemble necessary equipment 
Have patient sit (or lie) as upright as possible on edge of bed or in chair. This technique may be done supine or 
semi fowlers depending on patient situation.  Assess for c-spine stabilization and ensure that head and neck are 
supported if an assisted cough is to be performed. 
Place nose clip 
Establish with patient the signal he/she will use to notify you that MIC is reached (blinking for example) 

 
Protocol Version_ Extension Amendment 3, 4 June 2015 
 
32
Ask patient to take a breath in and holdand exhale completely before beginning first breath in with self inflating 
bag. 
Ask patient to place lips tightly around mouthpiece  
Gently squeeze the resuscitation bag, coordinating with the patient’s inspiration. Assess for leaks throughout the 
manoeuvre. 
Squeeze the bag 2-5 times until you feel that the lungs are full (assess chest expansion etc) or until the patient 
indicates with a signal that MIC is reached. 
Patient may feel a stretch in the chest or slight discomfort 
Monitor patient for any adverse symptoms: light-headedness, chest pain. If present, notify physician.  
Once the lungs are full, remove mouthpiece and ask the patient to hold the maximum insufflation for 2-5 
seconds if possible. 
Exhale slowly, preferably through pursed lips, or measure PCF ( LVR assisted) and MIC 
Repeat steps 5-11 three to five times. 
If secretions are present, ask the patient to produce a strong cough from maximum insufflation capacity. 
 
Note: 
For very young patients steps 5 and 10 are very difficult.  Children will generally wait to take a breath in once 
the mouth piece is in place.  They also tend to exhale as soon as the mouthpiece is removed. As they get older 
and more used to the technique you can add these steps in.  Remember the total respiratory cycle is much 
shorter than an adult’s, especially for those with compromised lung function who compensate with an increased 
respiratory rate.  A breath hold for a very stiff lung after breath stacking may be too difficult for some children.  
You will need to modify the cycles and instructions for each child. The most important thing is to achieve MIC 
at least 3 times per session. 
 
Sessions are usually performed: 
With assisted cough BID and prn if secretions are present…a maximum of Q10 minutes (avoid 
hyperventilation!) 
Ideally before meals and at bedtime 
 
References 
Carol Leblanc RRT, Lung Volume Recruitment for Paralytic/Restrictive Disorders Ottawa Hospital Respiratory 
Therapy Policy/Procedure, April 2007 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Protocol Version_ Extension Amendment 3, 4 June 2015 
 
33
APPENDIX 7. DATA-LOGGER TO MONITOR ADHERENCE 
 
Technology: 
The device recording the LVR manoeuvre mechanically will be activated when two pressure switches are 
closed. One switch will close when a minimum pressure threshold is detected at the mouthpiece; the second 
switch will close when a minimum pressure threshold is detected at the bag.  It is only when both switches are 
closed, that a count will be recorded. This is so that if there is an inadequate seal at the mouthpiece or the bag is 
unintentionally squeezed, the device will not count it. The pressure switches chosen for this application are 
miniature adjustable pressure switches by Dwyer (Model #MDA-111). The recording component of the device 
will hold in its memory the number of counts until the memory is cleared. The recording device is an event data 
logger by Omega (Model # OM-CP-EVENT110). This data logger can record and store the date and time for 
13,000 counts continuously over an expected battery life of at least three months (maximum 6 months).  The 
device sensitivity will be individually set and confirmed to record accurately when a minimum pressure (5 cm 
H2O) is achieved in each patient prior to data collection. It was found through preliminary trials that the 
minimum pressure threshold that generally produced the best results was approximately 5 cmH2O.   The data 
will be downloaded using a USB interface and Windows software designed for this data logger (OM-CP-
IFC200).    
 
Study: 
Drs. McKim and Katz have recently completed a study investigating the performance of the data-logger 
measuring frequency of LVR treatment, as compared to records made by the nurses administering the treatment, 
in adult neuromuscular and spinal cord disease in-patients in the Ottawa Hospital Rehabilitation Centre. The full 
dataset contains 243 matched pairs of sessions from 19 treatment periods on 125 days from 8 patients.  
 
Analysis of the number of cycles recorded by nurses and by the counters showed agreement in 215 pairs 
(88.5%). There was not statistically significant evidence of a systematic difference between nurses and counters 
(Wilcoxon signed-rank test, p=0.531). The Spearman correlation coefficient (0.76) indicated substantial 
correlation, and the intra-class correlation coefficient (0.59) indicated moderate to substantial agreement. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Protocol Version_ Extension Amendment 3, 4 June 2015 
 
34
APPENDIX 8. RESCUE TREATMENT 
 
 
During acute respiratory exacerbations, subjects may use assisted cough techniques, including LVR with 
or without an abdominal thrust and/or mechanical in-exsufflator, even if they are in the control population, if 
deemed appropriate by the treating physician. Brief use of such treatment is unlikely to affect the primary 
outcome, and therefore is not a criterion for withdrawal from the study. Rescue treatment is typically initiated 
and carried out by clinical care teams during hospitalizations for respiratory exacerbations (Appendix 4), which 
are expected to occur less than once per year per patient and last, on average, two weeks. Patients and their 
families are not taught LVR manoeuvres during a hospitalization; therefore we do not feel that treatment with 
LVR during an acute hospitalization will contaminate the control group’s treatment regimens once they are 
discharged from hospital. The use of any rescue medications or treatments will be recorded for both treatment 
groups.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Protocol Version_ Extension Amendment 3, 4 June 2015 
 
35
APPENDIX 9:   Justification for co-variates in minimization analytical model 
 
Systemic steroids: It has been documented that boys 10-18 years of age with Duchenne muscular dystrophy 
(DMD) treated (with deflazacort have significantly better pulmonary function than boys not treated. 1 As this 
therapy is not uniformly applied in Canada2, often because it has significant side effects associated with it, it 
was necessary to minimize on steroid use or non-use. 
 
Baseline FVC: Pulmonary function in DMD has been shown in a longitudinal study to have an ascending, 
plateau, and descending phase during the course of the disease.3  Based on the inclusion criteria of age and 
range of FVC 30-70% of predicted, we expect that the majority of individuals will be in the descending phase of 
FVC decline. However, as baseline FVC may predict the expected rate of decline of FVC, it was included in the 
analytical model.  
 
Scoliosis: As scoliosis can result in significant chest wall restriction and contribute to restrictive lung disease, 
thereby reducing FVC, this too was included as a co-variate. 4 
 
Age: As pulmonary function decline and muscle weakness progress predictably with age3, this is an important 
variable in determining expected decline in pulmonary function. 
 
Ambulatory Status: As the progression from ambulation to wheelchair dependency is an important marker of 
disease progression and muscle weakness, this variable was included in the analytical model.5 Loss of 
ambulation may also be associated with development of scoliosis.6  
 
References 
 
 
1.  
Biggar WD, Harris VA, Eliasoph L, Alman B. Long-term benefits of deflazacort treatment for 
boys with Duchenne muscular dystrophy in their second decade. Neuromuscul Disord 2006 Apr;16(4):249-55. 
 
2.  
McMillan HJ, Campbell C, Mah JK. Duchenne muscular dystrophy: Canadian paediatric 
neuromuscular physicians survey. Can J Neurol Sci 2010 Mar;37(2):195-205. 
 
3.  
Rideau Y, Jankowski LW, Grellet J. Respiratory function in the muscular dystrophies. Muscle 
Nerve 1981 Mar;4(2):155-64. 
 
4.  
Panitch HB. The pathophysiology of respiratory impairment in pediatric neuromuscular diseases. 
Pediatrics 2009 May;123:Suppl-8. 
 
5.  
Bakker JP, De Groot IJ, Beelen A, Lankhorst GJ, Bakker JPJ, De Groot IJM, Beelen A, 
Lankhorst GJ. Predictive factors of cessation of ambulation in patients with Duchenne muscular dystrophy. Am 
J Phys Med Rehabil 2002 Dec;81(12):906-12. 
 
6.  
Kinali M, Main M, Eliahoo J, Messina S, Knight RK, Lehovsky J, Edge G, Mercuri E, Manzur 
AY, Muntoni F, Kinali M, Main M, Eliahoo J, Messina S, Knight RK, Lehovsky J, Edge G, Mercuri E, Manzur 
AY, Muntoni F. Predictive factors for the development of scoliosis in Duchenne muscular dystrophy. Europ J 
Paediatr Neurol 2007 May;11(3):160-6. 
 
 
 
 
 
 
 
 
 
 

 
Protocol Version_ Extension Amendment 3, 4 June 2015 
 
36
APPENDIX 10: RESPIRATORY SYMPTOM QUESTIONNAIRE 
 
Respiratory SYMPTOM questionnaire 
 
Administered by Research Assistant at Telephone Visit 
 
The purpose of this questionnaire is to obtain information about your child for the past 3 months. We are asking 
the same questions of each participant in the study. All the information will be kept confidential. 
 
Subject ID: __________  
 
 
 
Date Completed: ______________ 
 
PERSON COMPLETING THE QUESTIONNAIRE:   
Child’s mother:       Child’s father :           Female guardian         Male guardian 
 
In the past 3 month, has the child had any respiratory problems? 
 
Yes                                     No 
 
If yes did your child have a 
 
1. cold or runny nose  
2. cough apart from colds 
3. wheezy or whistling sounds in chest when he has a cold 
4. wheezy or whistling sounds in chest between colds 
5. attack of wheezing or chest congestion that has caused him/her to be short of breath 
6. any change in the volume or color of respiratory secretions 
7. experienced chest pain during LVR 
 
In the past 3 month, has the child had any cardiac problems? 
 
Yes                                     No 
 
If yes, did your child 
1. experienced chest pain at other times than during LVR 
2. palpitations(feeling that your heart is skipping beats) during LVR 
3. palpitations(feeling that your heart is skipping beats) other than during LVR 
 
In the past 3 month, has the child had any other symptoms? 
 
Yes                                     No 
 
If yes what were the symptoms? 
 
 
 
 
 
 
 
 

 
Protocol Version_ Extension Amendment 3, 4 June 2015 
 
37
 
 
 
 
In the past 3 months, has this child needed to visit a physician? 
 
Yes.  Number of times ________________       No 
 
If Yes  
 
Why did you visit the physician? 
 
 
 
 
 
 
 
In the past 3 months, has this child been admitted to the hospital? 
Yes,                                                                      No 
 
If yes: 
 
What hospital was your child admitted to? 
 
 
Why was your child admitted? 
 
 
Was your child in ICU during this visit? 
 
 
How long was your child in hospital? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Protocol Version_ Extension Amendment 3, 4 June 2015 
 
38
APPENDIX 11: LVR SATISFACTION QUESTIONNAIRE  
 
Administered by Research Assistant at Telephone Visit 
The purpose of this questionnaire is to obtain information about your child for the past 3 months. We are asking 
the same questions of each participant in the study. All the information will be kept confidential. 
 
Subject ID_________________ 
 
Date completed_____________ 
 
Person completing questionnaire : □ Participant 
□ Caregiver 
 
Following questions asked only for group randomized to the Conventional Treatment plus LVR 
 
 
How many minutes does it take you to do your lung volume recruitment (LVR) each session? 
_____________________ 
 
How many LVR sessions do you do per day? __________________ 
 
Does LVR help you to move / clear chest secretions? 
 
Yes  
 
 
 
 
No 
 
Can you be flexible in the location where LVR is performed? 
 
Yes  
 
 
 
 
No 
 
Are you comfortable in performing the  LVR technique? 
 
Yes  
 
 
 
 
No 
 
 
Are you satisfied with LVR therapy? 
 
Yes  
 
 
 
 
No 
 
  
 
__________________________________________________________________________________________
__________________________________________________________________ 
Any other comments ___________________________________________________________ 
_____________________________________________________________________________ 

 
Protocol Version_ Extension Amendment 3, 4 June 2015 
 
40
APPENDIX 12 SELF-REPORT USAGE QUESTIONNAIRE 
 
Reviewed  in clinic 
 
February 2015 
SUNDAY 
MONDAY 
TUESDAY 
WEDNESDAY 
THURSDAY 
FRIDAY 
SATURDAY 
1 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
 
2 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
 
3 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
 
4 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
 
5 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
 
6 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
SUCTION 
 
SECRETIONS 
 
*Sick 
 
7 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
SUCTION 
 
SECRETIONS 
 
*Sick 
 
8 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
9 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
10 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
11 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
12 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
13 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
14 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
15 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
16 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
17 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
18 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
19 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
20 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
21 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
22 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
23 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
24 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
25 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
26 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
27 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 
28 
 
LVR AM 
 
LVR PM 
 
CPAP/BiPAP 
 
NIV 
 
PYSIO 
 
Suction 
 
Secretions 
 
*Sick 

 
Protocol Version_ Extension Amendment 3, 4 June 2015 
 
41
 
 
 
*Sick 
 
cough / cough / headache / others ___________________________ 
 
 
cough / cough / headache / others ___________________________ 
 
 
cough / cough / headache / others ___________________________ 
 
 

 
Protocol Version_ Extension Amendment 3, 4 June 2015 
 
42
 
 
 
 
 
APPENDIX 13: PedsQL Generic Core 
 
 
The following Questionnaires will be administered biannually at Clinic Visits. English and French versions will 
be used where validated questionnaires are available. 
 
PedsQL Generic Core - Version 4.0 
 Child Report (ages 8 - 12) 
 Parent Report for Children (ages 8 - 12) 
 Parent Report for Young Children (ages 5 - 7) 
 Teen Report (ages 13 - 18) 
 Parent for Teen (ages 13 - 18) 
 
Peds QL Neuromuscular Module - Version 3.0 
 Child Report (ages 8 - 12) 
 Parent Report for Children (ages 8 - 12) 
 Parent Report for Young Children (ages 5 - 7) 
 Teen Report (ages 13 - 18) 
 Parent for Teen (ages 13 - 18) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Protocol Version_ Extension Amendment 3, 4 June 2015 
 
43
 
APPENDIX 14:–ADVERSE EVENT DEFINITIONS 
 
Definitions 
 
The definitions of adverse events (AEs) and serious adverse events (SAEs) are given below.  It is of the 
utmost importance that all staff involved in the study are familiar with the content of this section.  The 
investigator at each site is responsible for ensuring this. 
 
Adverse Event   
 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical subject administered 
a treatment, which does not necessarily have to have a causal relationship with the treatment. 
 
An adverse event (AE) can therefore be any unfavourable and unintended sign (i.e. an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal product or therapy, 
whether or not considered related to the medicinal product or therapy. 
 
The phrase “responses to a medicinal product or therapy” means that a casual relationship between a medicinal 
product or therapy and an adverse event is at least a reasonable possibility, (i.e. the relationship cannot be ruled 
out) 

 
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APPENDIX 15: CASE REPORT (DATA COLLECTION) FORM 
 
Baseline Data Collection 
 
Inclusion and Exclusion met 
Consent date  
Randomization  
 Demographic data  
initials,  
DOB,  
gender 
Vital signs 
Height and weight, arm span 
Baseline Pulmonary function tests: FVC, MIP, MEP, MIC, PCF, LVR-assisted PCF and MIC 
Initial positive pressure setting 
 
Baseline Medical History   
Is Scoliosis present? If present: mild (0-10o), moderate (10-20o) severe (> 20o), Cobb angle (if available)  
Wheelchair dependent?  
 
Use of NPPV? 
If yes record the setting and length of use 
 
Use of In-EX at home?  
If yes record the setting and length of use 
Concomitant medications 
Quality of life Questionnaires  
 
Data Collection during Study – Clinic Visits at 6, 12, 18 and 24 months (4 visits) 
 
Vital Signs 
Height and weight 
Ambulatory status: Yes/No 
Scoliosis (annually) – Presence: Yes/No. If present: mild (0-10o), moderate (10-20o) severe (> 20o),  
 
Cobb angle (if available)  
Pulmonary function tests: FVC, MIP, MEP, MIC, PCF, LVR-assisted PCF and MIC 
Pressure measurement during LVR: maximal pressure achieved with LVR, average pressure achieved with 
LVR 
Number of times per day LVR done (if applicable) 
Physiotherapy – Frequency, suctioning required  
Re-assess use of LVR – retrain as necessary 
Collection of adverse events  
Concomitant medications 
Respiratory Symptom Review 
 
 
Quality of life Questionnaires (every 6 months) 
Data download from data-logger (for LVR Group) 
Symptom and satisfaction questionnaires (every 3 months) 
 
 
 
 

 
Protocol Version_ Extension Amendment 3, 4 June 2015 
 
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Data collection if ER visit and /or Hospital Admission  
 
Date of visit (admission) 
Date of Discharge 
Admitting Diagnosis 
Discharge diagnosis 
Was Lung Volume Recruitment used during this visit/admission? 
 
If yes – provide details 
Was the In-Exsufflator used during this visit/admission?   
If yes – provide details 
Medications received during Emergency/Hospital stay 
Procedures done 
Physio and RT time 
Adverse Events 
Respiratory Symptoms and exacerbations 
Courses of antibiotics for respiratory infections 
Hospitalization for respiratory infections 
Days in intensive care for respiratory exacerbations 
Days intubated and mechanically ventilated for respiratory exacerbations 
.