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Causal Mechanisms in Adolescent Arterial Stiffness

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ClinicalTrials.gov Identifier: NCT04128969
Recruitment Status : Recruiting
First Posted : October 16, 2019
Last Update Posted : April 13, 2023
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Justin Zachariah, Baylor College of Medicine

Brief Summary:
Hardening of the blood vessels, called arterial stiffness, is a risk factor for future heart disease and its causes are unclear. The proposed study will 1) randomly assign adolescents at high risk of stiffening blood vessels to take a protein supplement called carnitine and study its effects on arterial stiffening and 2) study carnitine related genes for their effect on arterial stiffening. The study will definitively establish a role for carnitine action as a cause of stiffening blood vessels and signal a way to treat or prevent stiffening.

Condition or disease Intervention/treatment Phase
Lipid Disorder Dyslipidemias Aortic Stiffness Insulin Resistance Syndrome Metabolic Syndrome Pediatric Obesity Dietary Supplement: CS+ Dietary Supplement: CS- Phase 2

Detailed Description:
Aortic stiffness measured in adolescence or adulthood determines current hypertension, predicts future incidence of hypertension, and future atherosclerotic cardiovascular disease (ASCVD) events. International hypertension guidelines list severe aortic stiffness as grounds to intensify anti-hypertensive pharmacotherapy. Mechanisms of arterial stiffness beyond aging and obesity warrant further elucidation. In our preliminary data from adolescents attending weight-loss summer camps arterial stiffness improvement was not associated with weight change but was with change in circulating carnitine. Carnitine influences fatty acid oxidation and carbohydrate metabolism. Carnitine could therefore link to arterial stiffness through insulin resistance which in turn affects cellular tone, vascular fibrosis, modification of lipids or glucose metabolism, and/or advanced glycation end products. This proposal leverages 2 instrumental variable study designs to infer a causal relation between carnitine and arterial stiffness. First, in 90 youth 11-21 years old at risk of arterial stiffening due to high serum triglycerides(TG), we will conduct a mechanistic, double blinded, randomized controlled trial for the effect of 6 months of oral carnitine supplementation (CS+, n=45) versus placebo (CS-, n=45) on aortic stiffness measured as carotid femoral pulse wave velocity (CFPWV); serum fatty acid oxidation biomarkers by metabolomics analysis; insulin resistance as homeostatic model assessment of insulin resistance (HOMA-IR); and TG. Aim 1 is to compare CS+ versus CS- on change in arterial stiffness and monitor adverse events. The hypothesis CS+ is associated with lower arterial stiffening, and CS+ effect is not modified by sex or race/ethnicity. Aim 2 is to compare the effect of CS+ versus CS- on fatty acid metabolism, insulin resistance, and lipids. The hypothesis is that CS+ alters long chain fatty acid beta oxidation, measured as lower long chain acylcarnitines, which in turn improves (HOMA-IR), and in turn decreases TG levels. This causal chain will be disentangled for direct versus indirect effects on CFPWV change. Second, naturally randomly assorted carnitine single nucleotide polymorphisms (SNPs) noted above will be used to characterize the relationship of carnitine to arterial stiffness and stratify the effectiveness of CS+.Aim 3a is to obtain the direct effect of carnitine on arterial stiffness using Mendelian randomization of SNPs associated with serum carnitine as instrumental variables with the hypothesis these variant SNPs are associated with lower arterial stiffness, supporting a causal inference. Aim 3b is to identify effect modification of CS+ vs CS- on arterial stiffness by examining if a carnitine genetic risk score will modify the effect of CS+ on change in arterial stiffness. This proposal with 2 instrumental variable projects would evaluate a causal role for carnitine in arterial stiffness at a point when the life course trajectory to hypertension can be modified. The study will also investigate the role of carnitine in insulin resistance and dyslipidemia at this same age, which may serve as grounds for future therapeutic clinical trials. Discovering genetically mediated causes of arterial stiffness or other outcomes may facilitate targeting of future therapies on susceptible youth before atherosclerotic changes are irreversible.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Causal Mechanisms in Adolescent Arterial Stiffness
Actual Study Start Date : February 1, 2020
Estimated Primary Completion Date : May 30, 2024
Estimated Study Completion Date : August 30, 2024

Arm Intervention/treatment
Experimental: Carnitine supplementation (CS+)
Carnitine supplementation in liquid form, sugar free.
Dietary Supplement: CS+
Oral carnitine supplementation

Placebo Comparator: Placebo (CS-)
Placebo comparator liquid similar in appearance and taste to CS+.
Dietary Supplement: CS-

Primary Outcome Measures :
  1. Change in Carotid Femoral Pulse Wave Velocity [ Time Frame: 6 months ]
    Carotid Femoral Pulse Wave Velocity will be measured noninvasively using applanation tonometry.

Secondary Outcome Measures :
  1. Change in Fasting Triglyceride [ Time Frame: 6 months ]
    Fasting serum triglycerides to be measured using conventional techniques.

  2. Change in Insulin Resistance [ Time Frame: 6 month ]
    Insulin resistance will be assessed using fasting serum glucose and fasting serum insulin to calculate homeostatic model assessment of insulin resistance.

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Ages Eligible for Study:   11 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. 11-21 year old adolescents
  2. males and females
  3. all ethnicities and races
  4. fasting serum triglyceride levels over 130 and less than 500 mg/dL
  5. fasting low density lipoprotein cholesterol (LDL-C) less than 160mg/dL.

Exclusion Criteria:

  1. known seizure disorder
  2. renal failure patients requiring renal replacement therapy like dialysis or renal transplant
  3. diabetes mellitus type 1 or 2
  4. congenital heart disease requiring surgical or catheterization intervention
  5. current pregnancy or planned pregnancy during the active study participation
  6. incarceration/institutionalized/wards of the state
  7. known metabolic disorders that require carnitine therapy
  8. nonadherence to study protocol during run-in phase defined as possessing 25% more than the expected remainder of placebo supplement pro-rated to the day of assessment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04128969

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Contact: Sandra Pena, CCRP 832-826-2806 sypena@texaschildrens.org
Contact: David Garuba 832-826-5925 garuba@bcm.edu

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United States, Texas
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Sandra Pena, CCRP    832-826-2806    sypena@texaschildrens.org   
Contact: Justin Zachariah, MD MPH    832-826-1280    justin.zachariah@bcm.edu   
Sponsors and Collaborators
Baylor College of Medicine
National Heart, Lung, and Blood Institute (NHLBI)
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Principal Investigator: Justin P Zachariah, MD MPH Study Principal Investigator
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Responsible Party: Justin Zachariah, Principal Investigator. Assistant Professor in Pediatrics, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT04128969    
Other Study ID Numbers: H-45557
R01HL148217 ( U.S. NIH Grant/Contract )
First Posted: October 16, 2019    Key Record Dates
Last Update Posted: April 13, 2023
Last Verified: April 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Justin Zachariah, Baylor College of Medicine:
arterial stiffness
pediatric obesity
metabolic syndrome
insulin resistance
Additional relevant MeSH terms:
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Metabolic Syndrome
Insulin Resistance
Pediatric Obesity
Lipid Metabolism Disorders
Pathologic Processes
Nutrition Disorders
Body Weight
Glucose Metabolism Disorders
Metabolic Diseases