Stacking Exercises Aid the Decline in FVC and Sick Time (STEADFAST)

Stacking Exercises Attenuate the Decline in Forced Vital Capacity and Sick Time (STEADFAST)

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.

Study Overview

• Status: Completed
• Conditions: Duchenne Muscular Dystrophy
• Intervention / Treatment: Other: Conventional Treatment; Device: Lung Volume Recruitment (LVR)

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.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Alberta Children's Hospital
    • Edmonton, Alberta, Canada, TGG 2J3
      • Stollery Children's Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • BC Children's Hospital
  • Ontario
    • Hamilton, Ontario, Canada, L8S 4K1
      • McMaster University
    • London, Ontario, Canada, N6A 4G5
      • London Health Sciences
    • Ottawa, Ontario, Canada, K1H 8L1
      • Children's Hospital of Eastern Ontario
    • Toronto, Ontario, Canada, M4G 1R8
      • Holland Bloorview Kids Rehabilitation Hospital
    • Toronto, Ontario, Canada, M5G 1X8
      • SickKids Hospital
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Hopital Ste. Justine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 16 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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% )

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Conventional Treatment	Other: 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
Active Comparator: Lung Volume Recruitment; Conventional treatment plus the use of Lung Volume Recruitment (LVR) twice per day	Other: 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; Device: Lung Volume Recruitment (LVR); LVR will be used twice per day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative decline in FVC (%-predicted) over 2 years, measured according to American Thoracic Society (ATS) standards, using the Stanojevic normative equations.	Relative decline 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 decline is an appropriate clinical laboratory measure and valid surrogate endpoint to use for this trial.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to FVC decline of 10% of predicted.		2 years
Total number and duration of outpatient oral antibiotic courses, hospital and ICU admissions for respiratory exacerbations over 2 years		2 years
Health-related quality of life over 2 years	Measured biannually with PedsQL 4.0, Pediatric Quality of Life Inventory	2 years
Change in unassisted peak cough flow (PCF), maximal insufflation capacity (MIC), maximum inspiratory and expiratory pressures (MIP, MEP), as well as MIC and PCF with LVR, over 2 years		2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal and average pressure achieved with LVR (cmH2O)		2 years
Respiratory symptoms	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	2 years
Satisfaction with LVR	Satisfaction with LVR, as assessed every 3 months by phone	2 years

Collaborators and Investigators

• Sponsor: Children's Hospital of Eastern Ontario
• Collaborators: Jesse's Journey-The Foundation for Gene and Cell Therapy
• Investigators: Principal Investigator: Sherri Katz, MD, Children's Hospital of Eastern Ontario; Study Director: Ian MacLusky, MD, Children's Hospital of Eastern Ontario; Study Director: Nicholas Barrowman, PhD, Children's Hospital of Eastern Ontario

Publications and helpful links

General Publications

• Morrow B, Argent A, Zampoli M, Human A, Corten L, Toussaint M. Cough augmentation techniques for people with chronic neuromuscular disorders. Cochrane Database Syst Rev. 2021 Apr 22;4(4):CD013170. doi: 10.1002/14651858.CD013170.pub2.
• Katz SL, Mah JK, McMillan HJ, Campbell C, Bijelic V, Barrowman N, Momoli F, Blinder H, Aaron SD, McAdam LC, Nguyen TTD, Tarnopolsky M, Wensley DF, Zielinski D, Rose L, Sheers N, Berlowitz DJ, Wolfe L, McKim D. Routine lung volume recruitment in boys with Duchenne muscular dystrophy: a randomised clinical trial. Thorax. 2022 Aug;77(8):805-811. doi: 10.1136/thoraxjnl-2021-218196. Epub 2022 Mar 2.

Study record dates

Study Major Dates

• Study Start: March 1, 2013
• Primary Completion (Actual): November 22, 2018
• Study Completion (Actual): November 22, 2018

Study Registration Dates

• First Submitted: November 14, 2013
• First Submitted That Met QC Criteria: November 25, 2013
• First Posted (Estimate): December 3, 2013

Study Record Updates

• Last Update Posted (Actual): December 24, 2018
• Last Update Submitted That Met QC Criteria: December 21, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: Duchenne Muscular Dystrophy; Pulmonary complications; Lung volume recruitment,; Breath-stacking,; Cough efficacy,; Maximal insufflation capacity
• Additional Relevant MeSH Terms: Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Muscular Disorders, Atrophic; Muscular Dystrophies; Muscular Dystrophy, Duchenne
• Other Study ID Numbers: 12/26E

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO