Marfan Syndrome and Loeys-Dietz Syndrome Moderate Exercise Trial II

Sponsor

Baylor College of Medicine (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05809323

Collaborator

Southern Star Research Pty Ltd. (Industry)

Enrollment

Location

Arms

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS) are distinct connective tissue disorders that both affect 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 or LDS 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 or LDS, 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 or LDS.

Condition or Disease	Intervention/Treatment	Phase
Marfan Syndrome Loeys-Dietz Syndrome	Other: Exercise Intervention Group Other: Control Group	N/A

Detailed Description

Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS) are distinct connective tissue disorders with overlapping 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 or LDS 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 or LDS being sedentary. This lack of exercise and deconditioning likely have 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 or LDS, 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 or LDS.

The objective is to:

Randomize 50 patients with Marfan syndrome or Loeys-Dietz syndrome from ages 10-25 years to current status and care (controls) versus a moderate dynamic exercise intervention, then
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, muscular/physical assessment: manual muscle testing (MMT), functional balance, and pain assessment, 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

The interventional study will be conducted as a parallel study model, with 2 groups in total: Exercise Intervention Group (interventional group) and Current Care Group (control group). Baseline and follow up testing will occur in both groups at identical time intervals.The interventional study will be conducted as a parallel study model, with 2 groups in total: Exercise Intervention Group (interventional group) and Current Care Group (control group). Baseline and follow up testing will occur in both groups at identical time intervals.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Jul 1, 2023

Anticipated Primary Completion Date :

Jul 1, 2025

Anticipated Study Completion Date :

Jul 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Exercise Intervention Group Group of up to 50 patients will randomly allocated into an experimental group at a 4:1 ratio intervention to controls. The experimental group will receive all of the preliminary outcome measure testing (cardiovascular, musculoskeletal, and psychological screening) in addition to exercise intervention education, demonstration, and follow up to ensure compliance and safety.	Other: Exercise Intervention Group 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.
Other: Control Group Control group will be randomly allocated at a 4:1 ratio, intervention to controls.. The control group will receive all of the preliminary outcome measure testing (cardiovascular, musculoskeletal, and psychological screening) and will be instructed to continue with baseline physical activities. They will be asked to return for a reassessment of all baseline procedures (cardiovascular, musculoskeletal, and psychological screening).	Other: Control Group 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

Arm

Intervention/Treatment

Experimental: Exercise Intervention Group

Group of up to 50 patients will randomly allocated into an experimental group at a 4:1 ratio intervention to controls. The experimental group will receive all of the preliminary outcome measure testing (cardiovascular, musculoskeletal, and psychological screening) in addition to exercise intervention education, demonstration, and follow up to ensure compliance and safety.

Other: Exercise Intervention Group

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.

Other: Control Group

Control group will be randomly allocated at a 4:1 ratio, intervention to controls.. The control group will receive all of the preliminary outcome measure testing (cardiovascular, musculoskeletal, and psychological screening) and will be instructed to continue with baseline physical activities. They will be asked to return for a reassessment of all baseline procedures (cardiovascular, musculoskeletal, and psychological screening).

Other: Control Group

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

Outcome Measures

Primary Outcome Measures

Maximum VO2 [4 Months]
Maximum VO2 in ml/kg/minute will be collected via Exercise Stress Test. Range 30-85, higher is better.

Secondary Outcome Measures

Mean systolic blood pressure [4 Months]
mmHg, range 20-200, both low and high are abnormal, goal is age, sex and height-based, goal 10-50 percentile
Mean diastolic blood pressure [4 Months]
mmHg, range 20-150, both low and high are abnormal, goal is age, sex and height-based, goal 10-50 percentile
Mean pulse pressure [4 Months]
mmHg, systolic blood pressure minus diastolic blood pressure, range 30-70 mmHg, goal is normal range for age and sex
Weight [4 Months]
kg, range 50-300kg, lower is better, excluding underweight patients
BMI [4 Months]
kg/m2, lower is better generally, excluding pts with BMI <5% for age
Left ventricular strain by cardiac MRI [4 Months]
Continuous measure derived from post-processing MRI
Right ventricular strain by cardiac MRI [4 Months]
Continuous measure derived from post-processing MRI
Aortic root strain [4 Months]
Continuous measure %, higher is less stiff, Range 0-40
Aortic Root Distensibility [4 Months]
×10-3 mm Hg-1, Continuous measure, range 0.1-10
Aortic Root β-Stiffness index [4 Months]
No units, Range 0.1-90
Maximum aortic root dimension [4 Months]
Measured in cm, range 1-8cm
Aortic root z-score [4 Months]
No units, based on body surface area published references, range -3 to 25
Aortic pulse wave velocity from MRI [4 Months]
meters/second, range 0-30
Pulse wave velocity derived from applanation tonometry [4 Months]
meters/second, range 0-30
Augmentation index [4 Months]
%, range 1-90
Manual muscle testing score [4 Months]
Grade 0-5, higher is better
Reactive hyperemia index [4 Months]
no units, 0-4 range, higher is worse
Visual analog assessment of pain [4 Months]
no units, scale from 0-6, 6 is worse
Single Leg Stance Test [4 Months]
seconds, higher is better
Single limb squat test score [4 Months]
seconds, higher is better
Star Excursion Balance Test [4 Months]
%, range 0-100, higher is better
6M Timed Hop Test [4 Months]
milliseconds, range 1 to infinity, lower is better
Scale for Child Anxiety Related Emotional Disorders (SCARED) (ages 12-18 y) [4 Months]
41 item scale, each with 3 point Likert scale, scale is summed, range 0-123, higher is worse
Quality of Life Scale (QOLS) (ages 19-21 y) [4 Months]
16 items, each with 7 point Likert, higher is worse
Pediatric Quality of Life Scale (PedsQL) scale scores [4 Months]
reported in 3 domains, each reported on Likert scale, scaled to 0-100 scale, lower is worse
Children's Depression Inventory (CDI) 2 (ages 12-18 y) [4 Months]
28-item assessment that yields a Total Score, 2 scale scores, and 4 subscale scores. For each item, respondent is presented with 3 choices that correspond to 3 levels of symptomatology: 0 (absence of symptoms), 1 (mild or probable symptom), or 2 (definite symptom). Lower is better
Depression, Anxiety, & Stress Scale (DASS) (ages 19-21 y) [4 Months]
set of 3 self-report scales. Each scale contains 14 items, each with a 4-point severity/frequency scale, higher is worse

Eligibility Criteria

Criteria

Ages Eligible for Study:

10 Years to 25 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male and female patients diagnosed with Marfan syndrome (defined by Ghent criteria and either a pathogenic variant in FBN1 or ectopia lentis) OR Loeys-Dietz syndrome (defined by presence of characteristic clinical features and a pathogenic variant in TGFBR1, TGFBR2, TGFB2, TFGB3, SMAD2, or SMAD3)
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.