Duchenne Muscular Dystrophy
Conditions
Keywords
Duchenne Muscular Dystrophy, Pulmonary complications, Lung volume recruitment,, Breath-stacking,, Cough efficacy,, Maximal insufflation capacity
Brief summary
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.
Detailed description
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.
Interventions
DEVICELung Volume Recruitment (LVR)
LVR will be used twice per day
OTHERConventional Treatment
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
Sponsors
Jesse's Journey
Children's Hospital of Eastern Ontario
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to 16 Years
Healthy volunteers
No
Inclusion criteria
* Age 6-16 years - This age range was selected as there are accepted normative pulmonary function data 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. * 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. * 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 * Symptomatic cardiomyopathy (ejection fraction less than 50% )
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in FVC (%-Predicted) From Baseline to 2 Years. | 2 years | Change in FVC (%-predicted) was chosen as the primary outcome as it is a strong predictor of subsequent respiratory failure and mortality. Although survival is not a realistic endpoint for this trial, given expected mortality is less than 5% for the pediatric age group, FVC change is an appropriate clinical laboratory measure and valid surrogate endpoint to use for this trial. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| FVC Decline of 10% of Predicted | 2 years | The time to reach an FVC decline of 10% of predicted will be used to calculate a hazard ratio. |
| Number of Participants Prescribed Outpatient Oral Antibiotic Courses Between Baseline and 2 Years | 2 years | Total number of participants who received any antibiotic courses between baseline and two years |
| Health-related Quality of Life From Baseline to 2 Years | 2 years | Measured biannually using the Pediatric Quality of Life Inventory (PedsQL 4.0). The PedsQL includes four subscales: Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning. Each subscale is scored from 0 to 100, with higher scores indicating better health-related quality of life. A total score is computed by averaging all subscale scores. |
| Change in Difference Between Assisted and Unassisted Peak Cough Flow (PCF) From Baseline to 2 Years | 2 years | Change in the difference between assisted and unassisted peak cough flow (in liters per minute) from baseline to 2 years. |
| Change in Maximum Inspiratory Pressures (MIP), From Baseline to 2 Years | 2 years | Change in maximum inspiratory pressures (MIP, in centimeters of water), From Baseline to 2 Years |
| Change in Maximal Expiratory Pressures (MEP), From Baseline to 2 Years | 2 years | Change in maximal expiratory pressures (MEP, in liters), From Baseline to 2 Years |
| Change in Maximal Insufflation Capacity (MIC)-Vital Capacity (VC) From Baseline to 2 Years | 2 years | Change in maximal insufflation capacity (MIC)-vital capacity (VC) in liters from Baseline to 2 Years |
Other
| Measure | Time frame | Description |
|---|---|---|
| Maximal and Average Pressure Achieved With LVR (cmH2O) | 2 years | — |
| Respiratory Symptoms | 2 years | Mean rate of symptom months over the study period. Symptom months are months with any respiratory symptom. |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Conventional Treatment Conventional Treatment
Conventional Treatment: 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 | 30 |
| Lung Volume Recruitment Conventional treatment plus the use of Lung Volume Recruitment (LVR) twice per day
Lung Volume Recruitment (LVR): LVR will be used twice per day
Conventional Treatment: 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 | 36 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Became ineligible | 0 | 2 |
| Overall Study | Enrolled in drug trial | 3 | 1 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 7 |
Baseline characteristics
| Characteristic | Conventional Treatment | Lung Volume Recruitment | Total |
|---|---|---|---|
| Age, Continuous | 11.5 years | 11.5 years | 11.5 years |
| FVC | 85.6 %-predicted | 84.0 %-predicted | 84.8 %-predicted |
| Non-invasive ventilation | 2 Participants | 2 Participants | 4 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Scoliosis | 3 Participants | 6 Participants | 9 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 30 Participants | 36 Participants | 66 Participants |
| Steroid use | 27 Participants | 32 Participants | 59 Participants |
| Wheelchair assisted | 10 Participants | 11 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 36 |
| other Total, other adverse events | 0 / 30 | 3 / 36 |
| serious Total, serious adverse events | 0 / 30 | 0 / 36 |
Outcome results
Primary
Change in FVC (%-Predicted) From Baseline to 2 Years.
Change in FVC (%-predicted) was chosen as the primary outcome as it is a strong predictor of subsequent respiratory failure and mortality. Although survival is not a realistic endpoint for this trial, given expected mortality is less than 5% for the pediatric age group, FVC change is an appropriate clinical laboratory measure and valid surrogate endpoint to use for this trial.
Time frame: 2 years
Population: Of the 70 children randomized to a treatment arm, four children (n=3 in conventional treatment group; n=1 in LVR group) were excluded from the analyses as they did not have a reliable or reproducible pulmonary function test at baseline. All remaining children were included in the analyses except where no measurement was available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conventional Treatment | Change in FVC (%-Predicted) From Baseline to 2 Years. | -9.2 Mean difference in FVC %-predicted | Standard Deviation 17.3 |
| Lung Volume Recruitment | Change in FVC (%-Predicted) From Baseline to 2 Years. | -6.4 Mean difference in FVC %-predicted | Standard Deviation 15.7 |
p-value: 0.6895% CI: [-6.9, 10.7]ANCOVA
Secondary
Change in Difference Between Assisted and Unassisted Peak Cough Flow (PCF) From Baseline to 2 Years
Change in the difference between assisted and unassisted peak cough flow (in liters per minute) from baseline to 2 years.
Time frame: 2 years
Population: Of the 70 children randomized to a treatment arm, four children (n=3 in conventional treatment group; n=1 in LVR group) were excluded from the analyses as they did not have a reliable or reproducible pulmonary function test at baseline. All remaining children were included in the analyses except where no measurement was available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conventional Treatment | Change in Difference Between Assisted and Unassisted Peak Cough Flow (PCF) From Baseline to 2 Years | -2.6 PCF=liters per minute | Standard Deviation 32 |
| Lung Volume Recruitment | Change in Difference Between Assisted and Unassisted Peak Cough Flow (PCF) From Baseline to 2 Years | 44.9 PCF=liters per minute | Standard Deviation 65.6 |
Comparison: Difference in change in peak cough flow (L/min) from baseline to 2 years, between conventional treatment and intervention group.95% CI: [-1.92, 2.18]
Secondary
Change in Maximal Expiratory Pressures (MEP), From Baseline to 2 Years
Change in maximal expiratory pressures (MEP, in liters), From Baseline to 2 Years
Time frame: 2 years
Population: Of the 70 children randomized, 4 (n=3 in conventional treatment group; n=1 in LVR group) were excluded from the analyses as they did not have a reliable or reproducible baseline pulmonary function tests. Results are for the observed population, as missing data imputation was not feasible. Of the remaining children, missing data was as follows: MIP and MEP (3 in conventional arm, 5 in LVR arm). A total of 16 children in the conventional group and 17 in the LVR group had useable data for MEP.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conventional Treatment | Change in Maximal Expiratory Pressures (MEP), From Baseline to 2 Years | 5.5 cm H2O | Standard Deviation 17.1 |
| Lung Volume Recruitment | Change in Maximal Expiratory Pressures (MEP), From Baseline to 2 Years | 12.9 cm H2O | Standard Deviation 19.4 |
p-value: 0.98Mixed Models Analysis
Secondary
Change in Maximal Insufflation Capacity (MIC)-Vital Capacity (VC) From Baseline to 2 Years
Change in maximal insufflation capacity (MIC)-vital capacity (VC) in liters from Baseline to 2 Years
Time frame: 2 years
Population: Of the 70 children randomized to a treatment arm, four children (n=3 in conventional treatment group; n=1 in LVR group) were excluded from the analyses as they did not have a reliable or reproducible pulmonary function test at baseline. All remaining children were included in the analyses except where no measurement was available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conventional Treatment | Change in Maximal Insufflation Capacity (MIC)-Vital Capacity (VC) From Baseline to 2 Years | 0.1 MIC-VC=Liter | Standard Deviation 0.2 |
| Lung Volume Recruitment | Change in Maximal Insufflation Capacity (MIC)-Vital Capacity (VC) From Baseline to 2 Years | 0.0 MIC-VC=Liter | Standard Deviation 0.2 |
p-value: 0.79Mixed Models Analysis
Secondary
Change in Maximum Inspiratory Pressures (MIP), From Baseline to 2 Years
Change in maximum inspiratory pressures (MIP, in centimeters of water), From Baseline to 2 Years
Time frame: 2 years
Population: Of the 70 children randomized, 4 (n=3 in conventional treatment group; n=1 in LVR group) were excluded from the analyses as they did not have a reliable or reproducible baseline pulmonary function tests. Results are for the observed population, as missing data imputation was not feasible. Of the remaining children, missing data was as follows: MIP and MEP (3 in conventional arm, 5 in LVR arm). A total of 16 children in the conventional group and 17 in the LVR group had useable data for MIP.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conventional Treatment | Change in Maximum Inspiratory Pressures (MIP), From Baseline to 2 Years | -0.5 cm H2O | Standard Deviation 15.7 |
| Lung Volume Recruitment | Change in Maximum Inspiratory Pressures (MIP), From Baseline to 2 Years | -4.6 cm H2O | Standard Deviation 25.1 |
p-value: 1Mixed Models Analysis
Secondary
FVC Decline of 10% of Predicted
The time to reach an FVC decline of 10% of predicted will be used to calculate a hazard ratio.
Time frame: 2 years
Population: Of the 70 children randomized to a treatment arm, four children (n=3 in conventional treatment group; n=1 in LVR group) were excluded from the analyses as they did not have a reliable or reproducible pulmonary function test at baseline. All remaining children were included in the analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conventional Treatment | FVC Decline of 10% of Predicted | 19.14 Months (restricted mean) | Standard Error 1.59 |
| Lung Volume Recruitment | FVC Decline of 10% of Predicted | 21.70 Months (restricted mean) | Standard Error 1.22 |
Secondary
Health-related Quality of Life From Baseline to 2 Years
Measured biannually using the Pediatric Quality of Life Inventory (PedsQL 4.0). The PedsQL includes four subscales: Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning. Each subscale is scored from 0 to 100, with higher scores indicating better health-related quality of life. A total score is computed by averaging all subscale scores.
Time frame: 2 years
Population: Participants who received either Conventional Treatment or Conventional Treatment plus LVR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Conventional Treatment | Health-related Quality of Life From Baseline to 2 Years | 2.0 score on a scale |
| Lung Volume Recruitment | Health-related Quality of Life From Baseline to 2 Years | 3.8 score on a scale |
Secondary
Number of Participants Prescribed Outpatient Oral Antibiotic Courses Between Baseline and 2 Years
Total number of participants who received any antibiotic courses between baseline and two years
Time frame: 2 years
Population: Of the 70 children randomized to a treatment arm, four children (n=3 in conventional treatment group; n=1 in LVR group) were excluded from the analyses as they did not have a reliable or reproducible pulmonary function test at baseline. All remaining children were included in the analyses except where no measurement was available.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Conventional Treatment | Number of Participants Prescribed Outpatient Oral Antibiotic Courses Between Baseline and 2 Years | 1 Participants |
| Lung Volume Recruitment | Number of Participants Prescribed Outpatient Oral Antibiotic Courses Between Baseline and 2 Years | 2 Participants |
Other Pre-specified
Maximal and Average Pressure Achieved With LVR (cmH2O)
Time frame: 2 years
Population: Data not collected during the study.
Other Pre-specified
Respiratory Symptoms
Mean rate of symptom months over the study period. Symptom months are months with any respiratory symptom.
Time frame: 2 years
Population: Respiratory symptoms were collected by telephone every 3 months over the study period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conventional Treatment | Respiratory Symptoms | 0.08 Months | Standard Deviation 0.14 |
| Lung Volume Recruitment | Respiratory Symptoms | 0.12 Months | Standard Deviation 0.29 |