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NCT Number: NCT05809323

Marfan Syndrome Moderate Exercise Trial II

Marfan syndrome (MFS) is a distinctive connective tissue disorder that affects multiple organ systems including the heart, bones, ligaments, and eyes, and is associated with significant risk of aortic dissection. Given limited evidence from in-vitro studies, and theoretical concerns, the majority of patients with MFS are restricted from certain physical activities. The lack of exercise and deconditioning have detrimental effects including increasing weakness, joint pain, decreased endurance, and depressive symptoms. Given the significant paucity of data currently existing on the effects of exercise in humans with MFS, and the recent, optimistic findings in rodent models, this pilot trial was established to assess the effects of moderated dynamic exercise in adolescents and young adults with MFS.

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Key information

Conditions

Marfan Syndrome Abnormalities, Multiple Bone Diseases Bone Diseases, Developmental Cardiovascular Abnormalities Cardiovascular Diseases Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Connective Tissue Diseases Genetic Diseases, Inborn Heart Defects, Congenital Heart Diseases Musculoskeletal Diseases Skin and Connective Tissue Diseases

Age range

10 year–25 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

About this study

Marfan syndrome (MFS) is a distinctive connective tissue disorder with clinical phenotypes that affect multiple organ systems including the heart, bones, ligaments, and eyes, and are associated with significant risk of aortic dissection. Given anecdotal reports of aortic dissection, limited evidence from in-vitro studies, and theoretical concerns, the majority of patients with MFS are restricted from certain physical activities, most commonly isometric exercise and contact sports. Published guidelines also suggest restriction from highly dynamic competitive sports. While clinicians may mean to restrict patients only from competitive sports, often children and families interpret this caution as applying to almost all exercise, resulting in a large number of patients with MFS being sedentary. This lack of exercise and deconditioning likely has detrimental effects in increasing weakness and joint pain and decreasing endurance. Depressive symptoms are also not uncommon in patients with these syndromes, and may be triggered or exacerbated by guidance to acutely cease participation in sports at the time of diagnosis.

To date, as far as we are aware, there are no published controlled studies on the effects of dynamic exercise on human subjects. In 2017, Mas-Stachurska et al published a study suggesting that a moderate level of dynamic exercise mitigated progressive degradation of the cardiac structures typically seen in MFS in a rodent sample. This study suggests the possibility that the fears surrounding moderate exercise in humans may be unwarranted. In addition, this study suggests that moderate exercise may actually protect the aorta and myocardium, in addition to the numerous other physical and emotional benefits that have been shown to result from consistent exercise. We have unpublished trial results in a pilot study that also suggest benefit to adolecents and young adults.

Given the significant paucity of data currently existing on effects of exercise in humans with MFS, and the recent optimistic findings in rodent models, we plan to conduct a randomized control trial of moderate dynamic exercise in adolescents and young adults with MFS.

The objective is to:

  • Randomize 50 patients with Marfan syndrome from ages 10-25 years to current status and care (controls) versus a moderate dynamic exercise intervention, then 2) allow the control group patients to undergo the exercise intervention.The investigators will then compare outcomes between both the intervention and control groups, and between the baseline and post-intervention states. Specific outcome measures will include cardiovascular assessment: maximal oxygen uptake (max VO2), ambulatory blood pressure, segmental and central aortic stiffness, ventricular mass and volume, and endothelial function, physical assessment by the physical therapist, and quality of life/mental health assessment: health-related quality of life, depression and anxiety screening scales. The hypothesis is that the intervention of a moderate exercise program introduced by a licensed physical therapist will result in improvement in cardiovascular status, muscular health, and mental health without detrimental effects on the aortic wall.

Who can participate

Healthy volunteers accepted: No

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

Inclusion criteria

  • Male and female patients diagnosed with Marfan syndrome (defined by Ghent criteria and either a pathogenic variant in FBN1 or ectopia lentis)
  • Age 10-25 years at enrollment

Exclusion criteria

  • History of aortic surgery
  • History of spinal surgery with implanted materials that may negatively impact MRI safety or imaging quality.
  • Diagnosis of major congenital heart disease (ASD, VSD, bicuspid aortic valve, and mitral valve prolapse will not qualify as exclusion criteria)
  • Condition limiting the ability to perform moderate exercise.
  • Major concurrent diagnosis that may confound the interpretation of the effect of the proposed intervention on the proposed outcome measures.
  • Aortic dilation meeting threshold for prophylactic aortic surgical intervention (>/= 4.5 cm in diameter)

Treatment and study plan

Exercise Intervention Group

Other

Patients will be educated on methods of self-evaluating exertion and cardiovascular effort by assessing respiratory rate and perceived exertion. Next, patients will be given options for cardiovascular activities and complete at a moderate level of activity for a minimum of 150 minutes per week. Patients will perform a combination of exercises under the supervision of a physical therapist until a mod intensity level is reached and sustained. Patients will be taught to use the activity tracker to record their heart rate, activity, and PES. Patients will have a phone call every week to assess status, answer questions, and provide guidance on progressing intensity or duration of exercise. At the end of 12 weeks all patients will return for re-assessment.

Control Group

Other

Patients in the control group will be instructed to continue with baseline physical activities over the duration of the study and be given instructions on the use of the activity tracker. At the end of 12 weeks all patients will return for re-assessment.

Other names: No Intervention

Primary outcomes

  1. Maximum VO2

    Time frame: 4 Months

    Maximum VO2 in ml/kg/minute will be collected via Exercise Stress Test. Range 30-85, higher is better.

Secondary outcomes

  1. Mean systolic blood pressure

    Time frame: 4 Months

    mmHg, range 20-200, both low and high are abnormal, goal is age, sex and height-based, goal 10-50 percentile

  2. Mean diastolic blood pressure

    Time frame: 4 Months

    mmHg, range 20-150, both low and high are abnormal, goal is age, sex and height-based, goal 10-50 percentile

  3. Mean pulse pressure

    Time frame: 4 Months

    mmHg, systolic blood pressure minus diastolic blood pressure, range 30-70 mmHg, goal is normal range for age and sex

  4. Weight

    Time frame: 4 Months

    kg, range 50-300kg, lower is better, excluding underweight patients

  5. BMI

    Time frame: 4 Months

    kg/m2, lower is better generally, excluding pts with BMI <5% for age

  6. Left ventricular strain by cardiac MRI

    Time frame: 4 Months

    Continuous measure derived from post-processing MRI

  7. Right ventricular strain by cardiac MRI

    Time frame: 4 Months

    Continuous measure derived from post-processing MRI

  8. Aortic root strain

    Time frame: 4 Months

    Continuous measure %, higher is less stiff, Range 0-40

  9. Aortic Root Distensibility

    Time frame: 4 Months

    ×10-3 mm Hg-1, Continuous measure, range 0.1-10

  10. Aortic Root β-Stiffness index

    Time frame: 4 Months

    No units, Range 0.1-90

  11. Maximum aortic root dimension

    Time frame: 4 Months

    Measured in cm, range 1-8cm

  12. Aortic root z-score

    Time frame: 4 Months

    No units, based on body surface area published references, range -3 to 25

  13. Aortic pulse wave velocity from MRI

    Time frame: 4 Months

    meters/second, range 0-30

  14. Pulse wave velocity derived from applanation tonometry

    Time frame: 4 Months

    meters/second, range 0-30

  15. Quality of Life Scale (QOLS) (ages 19-21 y)

    Time frame: 4 Months

    16 items, each with 7 point Likert, higher is worse

  16. Pediatric Quality of Life Scale (PedsQL) scale scores

    Time frame: 4 Months

    reported in 3 domains, each reported on Likert scale, scaled to 0-100 scale, lower is worse

  17. Patient Health Questionnaire-9 (PHQ-9)

    Time frame: 4 Months

    Nine-item questionnaire that detects depression and the severity of the depression, scaled from 0-27, higher is worse

  18. Patient Health Questionnaire-4 (PHQ-4) Subset A: Anxiety

    Time frame: 4 Months

    Four-question test for anxiety and depression, scaled from 0-12 Subset A (Anxiety): Questions 1 & 2, which have a total PHQ 4 score range of 0 to 6. A score of 3 or greater is considered positive for screening purposes.

  19. Patient Health Questionnaire-4 (PHQ-4) Subset B: Depression

    Time frame: 4 Months

    Four-question test for anxiety and depression, scaled from 0-12, Subset B (Depression): Questions 3 & 4, which have a total PHQ 4 score range of 0 to 6. A score of 3 or greater is considered positive for screening purposes.

  20. Generalized Anxiety Disorder 7-item (GAD-7)

    Time frame: Every 2 Weeks for 4 Months

    Seven-item questionnaire that detects generalized anxiety disorder and the severity of the anxiety. GAD-7 total score for the seven items ranges from 0 to 21. Using a cut-off of 8 the GAD-7 has a sensitivity of 92% and specificity of 76% for diagnosis generalized anxiety disorder.

  21. Pediatric Symptom Checklist Parent (PSC)

    Time frame: 4 Months

    The Pediatric Symptom Checklist (PSC) is a 35 item questionnaire that helps identify and assess changes in emotional and behavioral problems in children. A positive score on the PSC or Y-PSC suggests the need for further evaluation by a qualified health. PSC-35-Youth, English & Spanish cut off score is, 30 or higher. In a Mexican-American sample, a cutoff score of 12 was shown to be most sensitive.

  22. Pediatric Symptom Checklist Child (PSC-Y)

    Time frame: 4 Months

    The Pediatric Symptom Checklist (PSC) is a 35 item questionnaire that helps identify and assess changes in emotional and behavioral problems in children. A positive score on the PSC or Y-PSC suggests the need for further evaluation by a qualified health. PSC-35-Youth, English & Spanish cut off score is, 30 or higher. In a Mexican-American sample, a cutoff score of 12 was shown to be most sensitive.

    PSC Subscales:

    Attention Problems, Internalizing Problems, Externalizing Problems

  23. Pediatric Symptom Checklist Child (PSC-Y): Attention Subscale

    Time frame: 4 Months

    The Pediatric Symptom Checklist (PSC) is a 35 item questionnaire that helps identify and assess changes in emotional and behavioral problems in children. A positive score on the PSC or Y-PSC suggests the need for further evaluation by a qualified health. PSC-35-Youth, English & Spanish cut off score is, 30 or higher. In a Mexican-American sample, a cutoff score of 12 was shown to be most sensitive.

    PSC Subscales:

    Attention Problems Subscale: Children with subscores greater than or equal to 7 usually have significant impairments in attention.

  24. Pediatric Symptom Checklist Child (PSC-Y): Internalizing Problems Subscale

    Time frame: 4 Months

    The Pediatric Symptom Checklist (PSC) is a 35 item questionnaire that helps identify and assess changes in emotional and behavioral problems in children. A positive score on the PSC or Y-PSC suggests the need for further evaluation by a qualified health. PSC-35-Youth, English & Spanish cut off score is, 30 or higher. In a Mexican-American sample, a cutoff score of 12 was shown to be most sensitive.

    PSC Subscales:

    Internalizing Problems Subscale: Children with subscores greater than or equal to 5 usually have significant impairments with anxiety or depression.

  25. Pediatric Symptom Checklist Child (PSC-Y): Externalizing Problems Subscale

    Time frame: 4 Months

    The Pediatric Symptom Checklist (PSC) is a 35 item questionnaire that helps identify and assess changes in emotional and behavioral problems in children. A positive score on the PSC or Y-PSC suggests the need for further evaluation by a qualified health. PSC-35-Youth, English & Spanish cut off score is, 30 or higher. In a Mexican-American sample, a cutoff score of 12 was shown to be most sensitive.

    PSC Subscales:

    Externalizing Problems Subscale: Children with subscores greater than or equal to 7 usually have significant problems with conduct.

  26. PROMIS Pediatric Self- Reported Psychological Stress

    Time frame: 4 Months

    PROMIS scores have a mean of 50 and standard deviation (SD) of 10 in a referent population. On the T-score metric, A score of 40 is one SD lower than the mean of the reference population. A score of 60 is one SD higher than the mean of the reference population. Better health is a lower score and worse health scores higher.

  27. PROMIS Parent Proxy Reported Psychological Stress- Parent Proxy

    Time frame: 4 Months

    PROMIS scores have a mean of 50 and standard deviation (SD) of 10 in a referent population. On the T-score metric, A score of 40 is one SD lower than the mean of the reference population. A score of 60 is one SD higher than the mean of the reference population. Higher score is worse health.

Study contacts

Contact information is provided by the study sponsor or research team.

Jennifer Bogardus, PT, MPT, PhD

CONTACT

[email protected]

713-794-2070

Shaine A Morris, MD, MPH

CONTACT

[email protected]

832-826-5692

Sponsors and collaborators

Lead sponsor

Baylor College of Medicine

Other

Collaborators

  • Southern Star Research

Registry information

Official study title

Clinical Trial On The Effects Of Moderate Physical Activity On Health And Well-Being In Adolescents And Young Adults With Marfan Syndrome

Important dates

Study start
2023
Primary completion
2025
Study completion
2027
First posted
Apr 12, 2023
Registry last updated
Jan 24, 2024

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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