Clinical trial NCT04972565: Dyspnea in Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorder
Official title: Evaluation and Management of Dyspnea in Hypermobile Ehlers-Danlos Syndrome (hEDS) and Hypermobility Spectrum Disorder (HSD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Hypermobile EDS (hEDS)
Hypermobility Syndrome
Keywords: Hypermobile Ehlers Danlos Syndrome
Hypermobility Spectrum Disorder
Dyspnea
Inspiratory Muscle Training
Exercise
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
First posted: 2021-07-22
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Hypermobile EDS and HSD participants will be randomized to an inspiratory muscle training group versus usual care. Baseline measures will be compared to 17 age and sex-matched healthy controls.
Primary purpose: TREATMENT

Brief summary: Individuals with hypermobile Ehlers-Danlos Syndrome (hEDS) and Hypermobility Spectrum Disorders (HSD) often experience dyspnea. Inspiratory Muscle Training (IMT) has been shown to improve dyspnea and respiratory muscle function; however, the impact of IMT in combination with whole-body exercise training on respiratory muscle strength, dyspnea, and daily function remains unknown. The objectives of this research are i) to evaluate dyspnea, respiratory muscle strength and function, ventilatory parameters, and health-related quality of life (HRQL) in individuals with hEDS and HSD compared to healthy age and sex-matched controls, ii) to explore the contributors to dyspnea during exercise with a specific focus on respiratory muscle structure and function in hEDS and HSD patients and healthy controls, and iii) to assess whether the combination of IMT and whole-body exercise training will be more effective than whole-body exercise training alone in improving participant outcomes in hEDS and HSD participants. It is hypothesized that i) hEDS and HSD participants will have lower respiratory muscle strength, higher peripheral airway resistance, lower HRQL, and higher anxiety and depression levels compared to healthy controls, ii) the contributors to increased exercise induced dyspnea will include decreased respiratory muscle strength, increased airway resistance, and greater prefrontal cortical neural activity, and iii) the combination of IMT and whole-body exercise training will be superior to whole-body training alone for improving dyspnea, respiratory muscle strength and endurance, aerobic capacity, HRQL, anxiety, and depression.

Detailed description: Thirty-four hEDS and HSD participants will be recruited from the University Health Network (Toronto, Canada). Participants will have baseline evaluations of dyspnea, pulmonary function tests (i.e., oscillometry, spirometry, and lung volumes), respiratory muscle structure and function (i.e., diaphragm ultrasound and respiratory muscle strength), HRQL, anxiety and depression. Symptom limited cardiopulmonary exercise testing will be utilized to quantify exertional dyspnea using the 10-item Borg dyspnea scale, 18-point qualitative dyspnea assessment scale, peak oxygen uptake (peak VO2), and assessment of dynamic ventilatory parameters. Neural activity in the pre-frontal cortex will be measured during cardiopulmonary exercise testing via functional near-infrared spectroscopy. These baseline measures will be compared to 17 age and sex-matched healthy controls. After baseline assessments, hEDS and HSD participants will be randomized to one of the following groups: i) Usual Care plus IMT: 8 weeks of whole-body exercises (standard care provided to hEDS and HSD patients at the University Health Network) plus a concurrent IMT intervention 5 times per week); ii) Usual Care: 8 weeks of whole-body exercises (as outlined above). After four and eight weeks, participants will have repeat assessments as described below.

Exertional dyspnea is a prevalent and troublesome symptom experienced by individuals living with hEDS and HSD. This study will provide a better understanding of the underlying contributors of dyspnea in hEDS and HSD patients, with a focus on respiratory muscle structure and function, prefrontal cortical neural activity, and ventilatory parameters, both at rest and with exertion.

Eligibility criteria: Inclusion Criteria:

* Adult participants (≥ 18 years of age)
* New referral to the GoodHope Exercise and Rehabilitation (GEAR) Program at the University Health Network
* Diagnosis of hEDS based on the 2017 diagnostic criteria or diagnosis of HSD (defined as generalized joint hypermobility, chronic pain, and systemic findings to suspect connective tissue underpinnings) with clinical verification by the EDS medical team

Exclusion Criteria:

* Genetic testing confirming the diagnosis of another type of EDS (i.e., vascular EDS, classical EDS)
* Any contraindication to exercise testing (i.e., unstable cardiac disease). Presence of cardiac pacemaker/implantable defibrillator or structural cardiac abnormalities on echocardiogram
* Recent respiratory infection (\< 1 month) or known diagnosis of obstructive (i.e., asthma, chronic obstructive pulmonary disease) or restrictive parenchymal lung disease
* History of pneumothorax, otitis media (fluid behind the ear drum), or rupture of tympanic membranes given risk with IMT
* Recent participation in formal exercise training or IMT program (within the last 3 months)
* Persistent symptoms or difficulty tolerating IMT (i.e., breathing difficulties and/or chest pain)
* Diagnosis of severe autonomic dysfunction or postural orthostatic tachycardia syndrome limiting daily physical activity or exercise
* Neuromuscular disease (i.e., myositis, diaphragm paralysis) that may interfere with IMT
* Insufficient English fluency to provide informed consent or ability to follow study protocols
* Self-reported pregnancy
* Inability to connect to the internet

Primary outcomes:
measure: Maximal Inspiratory Pressure
timeFrame: Change from baseline at 8 weeks
Secondary outcomes:
measure: Maximal Expiratory Pressure
timeFrame: Change from baseline at 8 weeks
measure: Respiratory Muscle Endurance
timeFrame: Change from baseline at 4 weeks and 8 weeks
measure: Inspiratory Muscle Training Workload
timeFrame: Through study completion, an average of 8 weeks
measure: Inspiratory Muscle Training Load
timeFrame: Through study completion, an average of 8 weeks
measure: Inspiratory Muscle Training Mean Power
timeFrame: Through study completion, an average of 8 weeks
measure: Inspiratory Muscle Training Mean Volume
timeFrame: Through study completion, an average of 8 weeks
measure: Medical Research Council Dyspnea Scale
timeFrame: Change from baseline at 8 weeks
measure: Borg Dyspnea Scale
timeFrame: Through study completion, an average of 8 weeks
measure: Borg Dyspnea Scale
timeFrame: Change from baseline at 8 weeks
measure: Qualitative Assessment of Dyspnea
timeFrame: Change from baseline at 8 weeks
measure: Qualitative Assessment of Dyspnea
timeFrame: Change from baseline at 4 weeks and 8 weeks
measure: Oscillometry
timeFrame: Change from baseline at 8 weeks
measure: Spirometry (Forced Vital Capacity)
timeFrame: Change from baseline at 8 weeks
measure: Spirometry (Forced Expiratory Volume in 1 Second)
timeFrame: Change from baseline at 8 weeks
measure: Lung Volumes (Total Lung Capacity)
timeFrame: Change from baseline at 8 weeks
measure: Lung Volumes (Inspiratory Capacity)
timeFrame: Change from baseline at 8 weeks
measure: Lung Volumes (Residual Volume)
timeFrame: Change from baseline at 8 weeks
measure: Diaphragm Thickness
timeFrame: Change from baseline at 8 weeks
measure: Diaphragm Thickening Fraction
timeFrame: Change from baseline at 8 weeks
measure: Peak Oxygen Uptake During Cardiopulmonary Exercise Testing
timeFrame: Change from baseline at 8 weeks
measure: Ventilatory Response During Cardiopulmonary Exercise Testing
timeFrame: Change from baseline at 8 weeks
measure: Heart Rate Response During Cardiopulmonary Exercise Testing
timeFrame: Change from baseline at 8 weeks
measure: Pre-frontal Cortical Neural Activity During Cardiopulmonary Exercise Testing
timeFrame: Change from baseline at 8 weeks
measure: Physical Activity Levels
timeFrame: Change from baseline at 4 weeks and 8 weeks
measure: Leisure-Time Exercise
timeFrame: Baseline
measure: Health-Related Quality of Life
timeFrame: Change from baseline at 8 weeks
measure: Depression, Anxiety and Stress Scale
timeFrame: Change from baseline at 8 weeks
measure: Participant Study Recruitment
timeFrame: Over the study period (8 weeks)
measure: Participant Retention in the Study
timeFrame: Over the study period (8 weeks)
measure: Adherence to Inspiratory Muscle Training Load
timeFrame: Over the intervention period (8 weeks)
measure: Adherence to Inspiratory Muscle Training Days
timeFrame: Over the intervention period (8 weeks)
measure: Adverse Events During Inspiratory Muscle Training Practice (Safety and Tolerability)
timeFrame: Over the intervention period (8 weeks)
measure: Participant Satisfaction with the IMT Intervention
timeFrame: Change from baseline at weeks 1, 4 and 8
Other outcomes:
measure: Electrocardiogram
timeFrame: Baseline
measure: Chest X-Ray
timeFrame: Baseline
measure: Body Mass Index
timeFrame: Change from baseline at 4 weeks and 8 weeks
measure: Waist Circumference
timeFrame: Change from baseline at 4 weeks and 8 weeks
measure: Demographic Data
timeFrame: Baseline
Locations:
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
Study officials:
affiliation: University Health Network/University of Toronto
name: Dmitry Rozenberg, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Reychler G, Liistro G, Pierard GE, Hermanns-Le T, Manicourt D. Inspiratory muscle strength training improves lung function in patients with the hypermobile Ehlers-Danlos syndrome: A randomized controlled trial. Am J Med Genet A. 2019 Mar;179(3):356-364. doi: 10.1002/ajmg.a.61016. Epub 2018 Dec 20.
citation: Hakim AJ, Grahame R. Non-musculoskeletal symptoms in joint hypermobility syndrome. Indirect evidence for autonomic dysfunction? Rheumatology (Oxford). 2004 Sep;43(9):1194-5. doi: 10.1093/rheumatology/keh279. No abstract available.
citation: Ayres JG, Pope FM, Reidy JF, Clark TJ. Abnormalities of the lungs and thoracic cage in the Ehlers-Danlos syndrome. Thorax. 1985 Apr;40(4):300-5. doi: 10.1136/thx.40.4.300.
citation: Morgan AW, Pearson SB, Davies S, Gooi HC, Bird HA. Asthma and airways collapse in two heritable disorders of connective tissue. Ann Rheum Dis. 2007 Oct;66(10):1369-73. doi: 10.1136/ard.2006.062224. Epub 2007 Apr 5.
citation: Gazit Y, Nahir AM, Grahame R, Jacob G. Dysautonomia in the joint hypermobility syndrome. Am J Med. 2003 Jul;115(1):33-40. doi: 10.1016/s0002-9343(03)00235-3.
citation: Chatzoudis D, Kelly TJ, Lancaster J, Jones TM. Upper airway obstruction in a patient with Ehlers-Danlos syndrome. Ann R Coll Surg Engl. 2015 Apr;97(3):e50-1. doi: 10.1308/003588414X14055925061793.