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NCT Number: NCT04972565

Dyspnea in Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorder

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.

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Key information

Conditions

Hypermobile EDS (hEDS) Behavior Dyspnea Ehlers-Danlos syndrome type 3 Hypermobility Syndrome Motor Activity Pathological Conditions, Signs and Symptoms Respiration Disorders Respiratory Tract Diseases Signs and Symptoms Signs and Symptoms, Respiratory

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

University Health Network

Toronto, Ontario, M5G 2C4, Canada

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Usual Care plus Inspiratory Muscle Training (IMT)

Behavioral

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.

Primary outcomes

  1. 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.

Secondary outcomes

  1. 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.

  2. 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).

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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).

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. Diaphragm Thickness

    Time frame: Change from baseline at 8 weeks

    The right hemi-diaphragm thickness will be measured using a 13 megahertz ultrasound transducer.

  19. 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.

  20. 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.

  21. 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.

  22. 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.

  23. 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.

  24. 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.

  25. 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).

  26. 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.

  27. 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.

  28. 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.

  29. 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.

  30. 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).

  31. 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.

  32. 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.

  33. 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.

Other outcomes

  1. 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.

  2. 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.

  3. 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.

  4. Waist Circumference

    Time frame: Change from baseline at 4 weeks and 8 weeks

    Waist circumference (cm) will be ascertained from clinical records.

  5. Demographic Data

    Time frame: Baseline

    A demographic questionnaire will be administered to collect information on age, sex, and ethnicity of the study participants.

Sponsors and collaborators

Lead sponsor

University Health Network, Toronto

Other

Registry information

Official study title

Evaluation and Management of Dyspnea in Hypermobile Ehlers-Danlos Syndrome (hEDS) and Hypermobility Spectrum Disorder (HSD)

Important dates

Study start
2021
Primary completion
2025
Study completion
2025
First posted
Jul 22, 2021
Registry last updated
Apr 2, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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