Marfan Syndrome Moderate Exercise Trial II

Marfan Syndrome Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05809323
• Other study ID #: H-53417
• Status: Recruiting
• Phase: N/A
• Start date: September 1, 2023
• Est. completion date: July 1, 2027

Study information

• Verified date: August 2023
• Source: Baylor College of Medicine
• Contact: Shaine A Morris, MD, MPH
• Phone: 832-826-5692
• Email: shainem[@]bcm.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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:

1) 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: July 1, 2027
• Est. primary completion date: July 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 10 Years to 25 Years

Eligibility

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:

1. History of aortic surgery

2. History of spinal surgery with implanted materials that may negatively impact MRI safety or imaging quality.

3. Diagnosis of major congenital heart disease (ASD, VSD, bicuspid aortic valve, and mitral valve prolapse will not qualify as exclusion criteria)

4. Condition limiting the ability to perform moderate exercise.

5. Major concurrent diagnosis that may confound the interpretation of the effect of the proposed intervention on the proposed outcome measures.

6. Aortic dilation meeting threshold for prophylactic aortic surgical intervention (>/= 4.5 cm in diameter)

Related Conditions & MeSH terms

• Marfan Syndrome
• Syndrome

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Texas Children's Hospital	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Baylor College of Medicine	Southern Star Research Pty Ltd.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum VO2	Maximum VO2 in ml/kg/minute will be collected via Exercise Stress Test. Range 30-85, higher is better.	4 Months
Secondary	Mean systolic blood pressure	mmHg, range 20-200, both low and high are abnormal, goal is age, sex and height-based, goal 10-50 percentile	4 Months
Secondary	Mean diastolic blood pressure	mmHg, range 20-150, both low and high are abnormal, goal is age, sex and height-based, goal 10-50 percentile	4 Months
Secondary	Mean pulse pressure	mmHg, systolic blood pressure minus diastolic blood pressure, range 30-70 mmHg, goal is normal range for age and sex	4 Months
Secondary	Weight	kg, range 50-300kg, lower is better, excluding underweight patients	4 Months
Secondary	BMI	kg/m2, lower is better generally, excluding pts with BMI <5% for age	4 Months
Secondary	Left ventricular strain by cardiac MRI	Continuous measure derived from post-processing MRI	4 Months
Secondary	Right ventricular strain by cardiac MRI	Continuous measure derived from post-processing MRI	4 Months
Secondary	Aortic root strain	Continuous measure %, higher is less stiff, Range 0-40	4 Months
Secondary	Aortic Root Distensibility	×10-3 mm Hg-1, Continuous measure, range 0.1-10	4 Months
Secondary	Aortic Root ß-Stiffness index	No units, Range 0.1-90	4 Months
Secondary	Maximum aortic root dimension	Measured in cm, range 1-8cm	4 Months
Secondary	Aortic root z-score	No units, based on body surface area published references, range -3 to 25	4 Months
Secondary	Aortic pulse wave velocity from MRI	meters/second, range 0-30	4 Months
Secondary	Pulse wave velocity derived from applanation tonometry	meters/second, range 0-30	4 Months
Secondary	Quality of Life Scale (QOLS) (ages 19-21 y)	16 items, each with 7 point Likert, higher is worse	4 Months
Secondary	Pediatric Quality of Life Scale (PedsQL) scale scores	reported in 3 domains, each reported on Likert scale, scaled to 0-100 scale, lower is worse	4 Months
Secondary	Patient Health Questionnaire-9 (PHQ-9)	Nine-item questionnaire that detects depression and the severity of the depression, scaled from 0-27, higher is worse	4 Months
Secondary	Patient Health Questionnaire-4 (PHQ-4) Subset A: Anxiety	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.	4 Months
Secondary	Patient Health Questionnaire-4 (PHQ-4) Subset B: Depression	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.	4 Months
Secondary	Generalized Anxiety Disorder 7-item (GAD-7)	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.	Every 2 Weeks for 4 Months
Secondary	Pediatric Symptom Checklist Parent (PSC)	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.	4 Months
Secondary	Pediatric Symptom Checklist Child (PSC-Y)	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	4 Months
Secondary	Pediatric Symptom Checklist Child (PSC-Y): Attention Subscale	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.	4 Months
Secondary	Pediatric Symptom Checklist Child (PSC-Y): Internalizing Problems Subscale	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.	4 Months
Secondary	Pediatric Symptom Checklist Child (PSC-Y): Externalizing Problems Subscale	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.	4 Months
Secondary	PROMIS Pediatric Self- Reported Psychological Stress	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.	4 Months
Secondary	PROMIS Parent Proxy Reported Psychological Stress- Parent Proxy	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.	4 Months