- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04972565
Dyspnea in Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorder
Evaluation and Management of Dyspnea in Hypermobile Ehlers-Danlos Syndrome (hEDS) and Hypermobility Spectrum Disorder (HSD)
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Estimated)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Dmitry Rozenberg, MD, PhD
- Phone Number: 7358 416-340-4800
- Email: dmitry.rozenberg@uhn.ca
Study Locations
-
-
Ontario
-
Toronto, Ontario, Canada, M5G 2C4
- Recruiting
- University Health Network
-
Contact:
- Dmitry Rozenberg, MD, PhD
- Phone Number: 7358 416-340-4800
- Email: dmitry.rozenberg@uhn.ca
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Usual Care plus Inspiratory Muscle Training (IMT)
Participants will attend the standard of care rehabilitation program offered to hEDS and HSD patients at the University Health Network. The program consists of i) an individualized home-based rehabilitation and exercise program (twelve weeks of aerobic, neuromotor, and resistance-based exercises), ii) a self-management education intervention, and iii) a community resource engagement plan. Furthermore, patients attend four on-site sessions (a baseline assessment and three follow-up visits). Participants in this group will also be provided with a personalized prescription for an IMT program for eight weeks to be performed in the home environment (two daily IMT sessions of 30 breaths, five days per week). Participants will be virtually supervised by the study team weekly with any adverse events closely monitored. Participants will receive instructions and feedback on how to optimize their home training efforts with direct observation of their IMT practice. |
Participants will receive usual care and will also be provided with a personalized prescription for an IMT program for 8 weeks.
Participants will perform two daily IMT sessions of 30 breaths (< 5 minutes/session), 5 days per week in their home environment.
IMT intensity will be progressed weekly by 5-10% of the baseline maximal inspiratory pressure if the Borg Dyspnea score is < 7.
|
No Intervention: Usual Care
Participants will participate in the standard of care rehabilitation program offered to hEDS and HSD patients at the University Health Network.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Maximal Inspiratory Pressure
Time Frame: Change from baseline at 8 weeks
|
Maximal inspiratory pressure will be evaluated using standard methods in the pulmonary function laboratory, with the highest value (cm H2O) taken within 10 percent of the other readings as per American Thoracic Society recommendations.
|
Change from baseline at 8 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Maximal Expiratory Pressure
Time Frame: Change from baseline at 8 weeks
|
Maximal expiratory pressure will be evaluated using standard methods in the pulmonary function laboratory, with the highest value (cm H2O) taken within 10 percent of the other readings as per American Thoracic Society recommendations.
|
Change from baseline at 8 weeks
|
Respiratory Muscle Endurance
Time Frame: Change from baseline at 4 weeks and 8 weeks
|
Respiratory muscle endurance (endurance time measured in seconds) will be assessed using a manual threshold loading device (Philips Threshold trainer).
|
Change from baseline at 4 weeks and 8 weeks
|
Inspiratory Muscle Training Workload
Time Frame: Through study completion, an average of 8 weeks
|
Total IMT workload per session (product of inspiratory muscle force and inhaled volume expressed in Joules) will be extracted from the IMT device in the experimental group.
|
Through study completion, an average of 8 weeks
|
Inspiratory Muscle Training Load
Time Frame: Through study completion, an average of 8 weeks
|
Inspiratory muscle training Load (cm H2O) will be abstracted from the IMT device in the experimental group.
|
Through study completion, an average of 8 weeks
|
Inspiratory Muscle Training Mean Power
Time Frame: Through study completion, an average of 8 weeks
|
Inspiratory muscle training mean power per breath (Watts) will be abstracted from the IMT device in the experimental group.
|
Through study completion, an average of 8 weeks
|
Inspiratory Muscle Training Mean Volume
Time Frame: Through study completion, an average of 8 weeks
|
Inspiratory muscle training mean volume per breath (Litres) will be abstracted from the IMT device in the experimental group.
|
Through study completion, an average of 8 weeks
|
Medical Research Council Dyspnea Scale
Time Frame: Change from baseline at 8 weeks
|
The Medical Research Council Dyspnea Scale will be used to assess the effect of breathlessness on daily activities.
The scale comprises five statements that describe the range of respiratory dyspnea from none (Grade 1) to severe with difficulties performing self-care (Grade 5).
|
Change from baseline at 8 weeks
|
Borg Dyspnea Scale
Time Frame: Through study completion, an average of 8 weeks
|
The 10-point Borg Dyspnea Scale will be used throughout the study to adjust the intensity of inspiratory muscle training sessions The lowest score (0) corresponds to the sensation of normal breathing (absence of dyspnea) and the highest score (10) corresponds to the maximum possible sensation of dyspnea.
|
Through study completion, an average of 8 weeks
|
Borg Dyspnea Scale
Time Frame: Change from baseline at 8 weeks
|
The 10-point Borg Dyspnea Scale will be used during cardiopulmonary exercise testing to characterize degree of dyspnea.
The lowest score (0) corresponds to the sensation of normal breathing (absence of dyspnea) and the highest score (10) corresponds to the maximum possible sensation of dyspnea.
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Change from baseline at 8 weeks
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Qualitative Assessment of Dyspnea
Time Frame: Change from baseline at 8 weeks
|
The 18-point Qualitative Dyspnea Scale will be ascertained at the end of cardiopulmonary exercise testing.
Participants will be presented with a list of 18 descriptors characterizing their dyspnea and will be asked to rank the top three.
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Change from baseline at 8 weeks
|
Qualitative Assessment of Dyspnea
Time Frame: Change from baseline at 4 weeks and 8 weeks
|
The 18-point Qualitative Dyspnea Scale will be ascertained at the end of respiratory muscle endurance testing.
Participants will be presented with a list of 18 descriptors characterizing their dyspnea and will be asked to rank the top three.
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Change from baseline at 4 weeks and 8 weeks
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Oscillometry
Time Frame: Change from baseline at 8 weeks
|
Oscillometry will be performed in the pulmonary function laboratory following the protocol from the European Respiratory Society.
|
Change from baseline at 8 weeks
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Spirometry (Forced Vital Capacity)
Time Frame: Change from baseline at 8 weeks
|
Spirometry (forced vital capacity) will be measured in the pulmonary function laboratory following the American Thoracic Society Guidelines.
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Change from baseline at 8 weeks
|
Spirometry (Forced Expiratory Volume in 1 Second)
Time Frame: Change from baseline at 8 weeks
|
Spirometry (forced expiratory volume in 1 second) will be measured in the pulmonary function laboratory following the American Thoracic Society Guidelines.
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Change from baseline at 8 weeks
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Lung Volumes (Total Lung Capacity)
Time Frame: Change from baseline at 8 weeks
|
Lung volumes (i.e., Total Lung Capacity) will be measured in the pulmonary function laboratory following the American Thoracic Society Guidelines.
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Change from baseline at 8 weeks
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Lung Volumes (Inspiratory Capacity)
Time Frame: Change from baseline at 8 weeks
|
Lung volumes (i.e., inspiratory capacity) will be measured in the pulmonary function laboratory following the American Thoracic Society Guidelines.
|
Change from baseline at 8 weeks
|
Lung Volumes (Residual Volume)
Time Frame: Change from baseline at 8 weeks
|
Lung volumes (i.e., Residual Volume) will be measured in the pulmonary function laboratory following the American Thoracic Society Guidelines.
|
Change from baseline at 8 weeks
|
Diaphragm Thickness
Time Frame: Change from baseline at 8 weeks
|
The right hemi-diaphragm thickness will be measured using a 13 megahertz ultrasound transducer.
|
Change from baseline at 8 weeks
|
Diaphragm Thickening Fraction
Time Frame: Change from baseline at 8 weeks
|
The right hemi-diaphragm thickening fraction will be measured using a 13 megahertz ultrasound transducer.
|
Change from baseline at 8 weeks
|
Peak Oxygen Uptake During Cardiopulmonary Exercise Testing
Time Frame: Change from baseline at 8 weeks
|
Cardiopulmonary exercise test-based assessment of peak oxygen uptake (VO2 peak) will be performed on a cycle ergometer.
|
Change from baseline at 8 weeks
|
Ventilatory Response During Cardiopulmonary Exercise Testing
Time Frame: Change from baseline at 8 weeks
|
Ventilatory response will be assessed during cardiopulmonary exercise testing (on a cycle ergometer) with exhaled gas measurements captured breath by breath.
|
Change from baseline at 8 weeks
|
Heart Rate Response During Cardiopulmonary Exercise Testing
Time Frame: Change from baseline at 8 weeks
|
Heart rate response will be assessed during cardiopulmonary exercise testing on a cycle ergometer.
|
Change from baseline at 8 weeks
|
Pre-frontal Cortical Neural Activity During Cardiopulmonary Exercise Testing
Time Frame: Change from baseline at 8 weeks
|
Oxygenated and total hemoglobin of the prefrontal cortex will be measured with Functional Near Infrared Spectroscopy during cardiopulmonary exercise testing.
|
Change from baseline at 8 weeks
|
Physical Activity Levels
Time Frame: Change from baseline at 4 weeks and 8 weeks
|
Physical activity (daily steps) will be measured via a tracking device (Fitbit, San Francisco, USA) for a 7-day period.
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Change from baseline at 4 weeks and 8 weeks
|
Leisure-Time Exercise
Time Frame: Baseline
|
Leisure-time exercise will be measured via the 3-item Godin Leisure-Time Exercise Questionnaire - Leisure Score Index.
The Leisure Score Index is used to rank individuals from the lowest to highest exercise levels: sedentary (score less than 14 units); moderately active (score of 14-23 units); and active (24 units or more).
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Baseline
|
Health-Related Quality of Life
Time Frame: Change from baseline at 8 weeks
|
The Short-Form 36 Health Survey (SF-36) will be used to assess general health-related quality of life.
The SF-36 consists of eight scaled scores (total score ranging from 0 to 100), with lower scores representing lower health-related quality of life.
|
Change from baseline at 8 weeks
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Depression, Anxiety and Stress Scale
Time Frame: Change from baseline at 8 weeks
|
The Depression, Anxiety and Stress Scale (DASS-21) questionnaire has 21 items to assess mood (anxiety, depression, and stress).
Each statement for the three domains is given a score of 0 (not applicable) to 3 (applicable most of the time) with scores categorized as follows: Normal, Mild, Moderate, Severe, and Extremely Severe.
|
Change from baseline at 8 weeks
|
Participant Study Recruitment
Time Frame: Over the study period (8 weeks)
|
Recruitment-success percentage and reasons for participation/non-participation in the study will be collected.
|
Over the study period (8 weeks)
|
Participant Retention in the Study
Time Frame: Over the study period (8 weeks)
|
Participant retention will be assessed by measuring participant follow-up with testing throughout the study period.
|
Over the study period (8 weeks)
|
Adherence to Inspiratory Muscle Training Load
Time Frame: Over the intervention period (8 weeks)
|
Adherence to the IMT intervention will be tracked electronically via the IMT device (i.e., percentage of the maximal inspiratory pressure prescribed).
|
Over the intervention period (8 weeks)
|
Adherence to Inspiratory Muscle Training Days
Time Frame: Over the intervention period (8 weeks)
|
Adherence to the IMT intervention will be tracked using a participant log to record the number of training days completed each week.
|
Over the intervention period (8 weeks)
|
Adverse Events During Inspiratory Muscle Training Practice (Safety and Tolerability)
Time Frame: Over the intervention period (8 weeks)
|
Any adverse events (i.e.
prolonged muscle soreness, pneumothorax) with IMT will be assessed throughout the study period.
|
Over the intervention period (8 weeks)
|
Participant Satisfaction with the IMT Intervention
Time Frame: Change from baseline at weeks 1, 4 and 8
|
A multiple-choice and free-form questionnaire assessing the participants' satisfaction with the IMT intervention will be completed by study participants.
|
Change from baseline at weeks 1, 4 and 8
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Electrocardiogram
Time Frame: Baseline
|
A 12-Lead Electrocardiogram will be performed in all study participants.
The following electrocardiogram parameter (i.e.
ST segment) will be assessed to ensure within normal limits before cardiopulmonary exercise testing to ensure no signs of active ischemia.
|
Baseline
|
Chest X-Ray
Time Frame: Baseline
|
Chest x-ray will be performed to characterize possible etiologies of dyspnea and exclude any evidence of pneumothorax prior to commencing an IMT program.
|
Baseline
|
Body Mass Index
Time Frame: Change from baseline at 4 weeks and 8 weeks
|
Body mass index data (kg/m^2) will be ascertained from clinical records.
|
Change from baseline at 4 weeks and 8 weeks
|
Waist Circumference
Time Frame: Change from baseline at 4 weeks and 8 weeks
|
Waist circumference (cm) will be ascertained from clinical records.
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Change from baseline at 4 weeks and 8 weeks
|
Demographic Data
Time Frame: Baseline
|
A demographic questionnaire will be administered to collect information on age, sex, and ethnicity of the study participants.
|
Baseline
|
Collaborators and Investigators
Investigators
- Principal Investigator: Dmitry Rozenberg, MD, PhD, University Health Network/University of Toronto
Publications and helpful links
General Publications
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Cardiovascular Diseases
- Vascular Diseases
- Skin Diseases
- Respiratory Tract Diseases
- Respiration Disorders
- Disease
- Congenital Abnormalities
- Hematologic Diseases
- Hemorrhagic Disorders
- Genetic Diseases, Inborn
- Connective Tissue Diseases
- Hemostatic Disorders
- Skin Diseases, Genetic
- Signs and Symptoms, Respiratory
- Skin Abnormalities
- Collagen Diseases
- Syndrome
- Dyspnea
- Ehlers-Danlos Syndrome
Other Study ID Numbers
- 20-6346
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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