A Phase 3 interventional study of Cold Stress and Maximal Dynamic Exercise in Down Syndrome and Autonomic Dysfunction, sponsored by University of Colorado, Denver. Recruiting at 1 site in United States. Open to participants aged 18 Years to 50 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-10-13.
Sponsored by University of Colorado, Denver · Phase 3, Interventional, and Prevention
Down syndrome (DS), the most common genetic cause of intellectual disability, is associated with widespread organ dysfunction, including abnormalities in the autonomic nervous system (ANS). The ANS regulates critical functions such as heart rate (HR) and blood pressure (BP), both essential for maintaining homeostasis and supporting physical activity. Individuals with DS often exhibit blunted HR responses to exercise-typically \~30 beats per minute below expected levels-suggesting reduced sympathetic nervous system (SNS) activity. The SNS governs rapid changes in HR and BP during stress by releasing catecholamines: epinephrine (from the adrenal medulla) and norepinephrine (from sympathetic nerve endings). Despite its importance, SNS function has not been comprehensively assessed among individuals with DS.
This study addresses a critical knowledge gap by evaluating SNS responses to physiological stressors in individuals with DS. The investigators will measure beat-to-beat HR and BP, along with plasma catecholamine levels, in response to sympathetic activation, comparing individuals with DS to age- and sex-matched controls. Understanding the mechanisms of SNS dysfunction in DS is vital, as it likely underlies reduced exercise capacity and contributes to broader clinical challenges. These insights may guide targeted interventions to improve cardiovascular function, physical capacity, and overall quality of life in this understudied population.
Evolution has equipped each species with instinctual defense mechanisms to cope with environmental stressors, ensuring survival. Many of these mechanisms are driven by activation of the sympathetic nervous system (SNS), which orchestrates the "fight or flight" response. Systemic SNS activation extends across all organ systems, triggering the release of catecholamines to elevate heart rate (HR) and increase blood pressure (BP) to meet the heightened metabolic demands of the stressor and ensure the delivery of oxygen-rich blood to active tissues. Exercise, a potent sympathoexcitatory stressor, poses a major challenge to the oxygen transport system, requiring coordinated organ system function to increase both HR and BP. Dysregulated SNS activation can impair oxygen delivery, leading to reduced work capacity, quality of life, and is an independent predictor of morbidity and premature mortality. Therefore, experimental approaches to understand SNS activation in populations with reduced work capacity and premature morbidity, mortality is of upmost importance for improving health outcomes and quality of life on a population level.
Down syndrome (DS) is the most common chromosomal abnormality in the human population, with widespread effects across numerous tissues and organ systems, including accelerated biological aging. Individuals with DS exhibit reduced work capacity, with maximal HRs \~30 beats below normal, and face higher rates of premature morbidity and mortality than the general population. Notably, individuals with DS demonstrate blunted catecholamine response to the sympathetic stressor of maximal exercise, suggesting diminished SNS activation. Recent literature from this PI suggests altered peripheral blood flow and BP regulation among individuals with DS during large muscle mass exercise which immolates walking, or running- critical for survival. These findings align with recent evidence of hypoxic signaling, elevated heme metabolism, and stress erythropoiesis across the lifespan in this population. Together, these data suggest that impaired oxygen delivery, potentially linked to SNS dysregulation, may be more widespread in DS than previously recognized.
However, the role of SNS activation in the context of daily stressors which elevate both HR and BP, remains unclear. Understanding the mechanisms underlying SNS dysfunction in DS is crucial, as it likely contributes to many clinical and developmental challenges, including the underlying reduced work capacity and suggested autonomic dysfunction observed in this population. Addressing this gap may enable targeted therapies to enhance survival, longevity, and quality of life for individuals with DS. The investigators aim to systematically evaluate SNS activation through four stressors which mimic common stressors faced to any individual over the course of a day or lifespan. Through evaluation of plasma catecholamines, the investigators hope to elucidate the mechanisms and impact of catecholamine responses in individuals with DS compared typical responses observed among individuals without DS.
Aim 1. Characterize the catecholamine response to physiological stressors among individuals with DS. The investigators will assess SNS responses in individuals with DS and age- and sex-matched controls. Beat-to-beat HR and BP, along with plasma catecholamine levels will be collected in response to the following sympathetic stressors: A) Cold Stress, B) Handgrip with Post-Exercise Muscle Ischemia, C) Head-up Tilt, and D) Maximal Dynamic Exercise (VO2peak). Metabolomics and proteomics will be performed on the plasma samples and these efforts will help define the manifestations of hormonal SNS dysfunction in individuals with DS.
438 studies on the registry are indexed under Down Syndrome; 99 are open to participants now.
This study's planned enrollment of 200 is above the median of 37 across 286 interventional studies indexed under Down Syndrome.
Browse Down Syndrome studies →University of Colorado, Denver is the lead sponsor of 1,543 studies on the registry; 317 are open to participants now.
Of its 147 completed or terminated interventional studies of FDA-regulated products, 92 (63%) have results posted.
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The criteria were revised on the registry on Sep 28, 2026. See what changed
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Specific Exclusion Criteria for Certain Stressors:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
BMI (body mass index)
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Postmenopausal
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The investigators will be recruiting participants between the ages of 18-50 for the study investigating responses to four sympathetic stressors compared to age and sex matched individuals without Down syndrome.
Other: Cold Stress · Other: Maximal Dynamic Exercise · Other: Isometric Handgrip Exercise with Post-Exercise Muscle Ischemia · Other: Head-up Tilt Table Test
The investigators will be recruiting individuals without Down syndrome between the ages of 18-50 to serve as the comparisons for individuals with Down syndrome across the four sympathetic stressors.
Other: Cold Stress · Other: Maximal Dynamic Exercise · Other: Isometric Handgrip Exercise with Post-Exercise Muscle Ischemia · Other: Head-up Tilt Table Test
Cold triggers the sympathetic nervous system, known as the 'fight-or-flight' response, which prepares the body to respond to a perceived threat by increasing heart rate, blood pressure, and releasing catecholamines. These measurements will be taken to examine how individuals with DS will respond during a cold stress test. The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during a cold stress test in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.
Also known as: Cold Pressor Test, Cold Water
The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during a treadmill maximal exercise test in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.
Also known as: VO2peak, Treadmill Exercise
The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during a isometric handgrip exercise followed by an ischemic period which will be induced by a blood pressure cuff in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.
Also known as: Handgrip, Post-Exercise Muscle Ischemia
The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during passive head-up tilt testing which is a standardized, noninvasive clinical and research procedure used to characterize cardiovascular autonomic responses to orthostatic stress, among individuals with Down syndrome, who have proposed autonomic dysfunction.
Also known as: Tilt Table, Orthostatic Stress
Seated Baseline Concentration of Plasma Catecholamines
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: Seated baseline blood draw, prior to stressors
Standing Baseline Concentration of Plasma Catecholamines
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: Blood draw will occur in standing position, prior to head up tilt table testing
Concentration of Plasma Catecholamines During Cold Pressor Test
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: During the cold stress test, around or up to 5 minutes
Concentration of Plasma Catecholamines During Handgrip Test
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: Blood draws occur around or up to 2-3 minutes into handgrip test
Concentration of Plasma Catecholamines During Post Exercise Muscle Ischemia
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: Seated blood draw to occur, around or about 2-3 minutes into post exercise muscle ischemia
Supine Concentration of Plasma Catecholamines
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: Blood draws during or around 10 minutes of supine rest
Supine Concentration of Plasma Catecholamines, 5 Minutes into Head-Up Tilt
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: At or around 5 minutes into the head-up tilt table stimulus
Supine Concentration of Plasma Catecholamines, 10 Minutes into Head-Up Tilt
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: At or around 10 minutes into the head-up tilt table stimulus
Baseline Standing Concentration of Plasma Catecholamines Prior to Maximal Exercise Test
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: Standing baseline blood draw, prior to maximal exercise test
Standing Concentration of Plasma Catecholamines at End of Maximal Exercise Test
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: This blood draw will occur at the very end or immediately following the maximal exercise test on the treadmill
Standing Concentration of Plasma Catecholamines, 30 Minutes Post Maximal Exercise
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: This blood draw will occur around 30 minutes following the maximal exercise test on the treadmill
Standing Concentration of Plasma Catecholamines, 60 Minutes Post Maximal Exercise
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: This blood draw will occur at the around 60 minutes following the maximal exercise test on the treadmill
Seated Baseline Heart Rate, Prior to Cold Pressor Test
Investigators will collect beat-to-beat heart rate recordings in all participants before, during (in some stressors), and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: Resting seated baseline, prior to cold pressor test, up to or around 5 minutes
Heart Rate Collected During Cold Pressor Test
Investigators will collect beat-to-beat heart rate recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: Collected throughout the Cold Pressor Test, around 6 minutes in total
Heart Rate, Maximal Exercise Test
Investigators will collect beat-to-beat heart rate recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: Continuous heart rate recordings will take place throughout the maximal aerobic exercise test on the treadmill, up to or around 20 minutes
Seated Baseline Blood Pressure, Prior to Cold Pressor Test
Investigators will collect beat-to-beat blood pressure recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: Resting seated baseline, prior to cold pressor test, up to or around 5 minutes
Blood Pressure Collected During Cold Pressor Test
Investigators will collect beat-to-beat blood pressure recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: Collected throughout the Cold Pressor Test, around 6 minutes in total
Heart Rate Collected During Handgrip with Post-Exercise Muscle Ischemia
Investigators will collect beat-to-beat heart rate recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: Collected throughout the Handgrip tests with Post-Exercise Muscle Ischemia, around 12 minutes in total
Heart Rate Collected During Head-Up Tilt Table Test
Investigators will collect beat-to-beat heart rate recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: Collected throughout the Head-Up Tilt Table Test, around 25 minutes in total
Blood Pressure Collected During Handgrip Test with Post-Exercise Muscle Ischemia
Investigators will collect beat-to-beat blood pressure recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: Collected throughout the handgrip test with post-exercise muscle ischemia, up to or around 12 minutes
Blood Pressure Collected During Head-Up Tilt Table Test
Investigators will collect beat-to-beat blood pressure recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Time frame: Collected throughout the head-up tilt table test, around 25 minutes in total
Facial Affective Scale Score, Baseline Assessment
Investigators will use the validated 'Facial Affective Scale', which uses a series of nine drawn faces showing various degrees of emotional distress to help participants assess their emotional state. The nine faces represent a range of negative to positive affect, and each face having a specific value between 0.04 (maximum positive affect) and 0.97 (maximum negative affect). The chosen face's corresponding value is the Facial Affective Score. This will take up to or around approximately 5 minutes to complete.
Time frame: Baseline Assessment of Facial Affective Scale, this will occur prior to any stressors.
Facial Affective Scale Score, Cold Pressor Test, 1.5 Minutes
Investigators will use the validated 'Facial Affective Scale', which uses a series of nine drawn faces showing various degrees of emotional distress to help participants assess their emotional state. The nine faces represent a range of negative to positive affect, and each face having a specific value between 0.04 (maximum positive affect) and 0.97 (maximum negative affect). The chosen face's corresponding value is the Facial Affective Score.
Time frame: Assessment occurs around or up to 90 seconds (1.5 minutes) into cold water immersion
Facial Affective Scale Score, Cold Pressor Test, Finale
Investigators will use the validated 'Facial Affective Scale', which uses a series of nine drawn faces showing various degrees of emotional distress to help participants assess their emotional state. The nine faces represent a range of negative to positive affect, and each face having a specific value between 0.04 (maximum positive affect) and 0.97 (maximum negative affect). The chosen face's corresponding value is the Facial Affective Score.
Time frame: Assessment occurs immediately following or during the last minute of the Cold Pressor Test, up to or around 6 minutes following placement of arm into cold
Plan to share: No
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