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Mitochondrial-targeted Antioxidant Supplementation for Improving Age-related Vascular Dysfunction in Humans

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ClinicalTrials.gov Identifier: NCT04851288
Recruitment Status : Recruiting
First Posted : April 20, 2021
Last Update Posted : July 21, 2022
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Douglas Seals, University of Colorado, Boulder

Study Description
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Brief Summary:

The majority of cardiovascular diseases (CVD) occur in men and women ≥60 years of age. Vascular dysfunction, including endothelial dysfunction, as assessed by reduced endothelium-dependent dilation (EDD), and stiffening of the large elastic arteries (i.e., aortic and carotid artery stiffening), is a major mechanism of increased risk of CVD in older adults. Excess production of ROS (reactive oxygen species) by mitochondria (mtROS) has emerged as a central feature of vascular oxidative stress with aging and driver of age-related vascular dysfunction. As such, identifying novel strategies to decrease mtROS and improve vascular function, to ultimately reduce the risk of age-related CVD, is an important biomedical objective.

MitoQ is a mitochondria-targeted antioxidant that accumulates at the inner mitochondrial membrane where it is optimally positioned to reduce mtROS. Preclinical findings showed that 4 weeks of oral MitoQ supplementation completely restored EDD in old mice, ameliorated mtROS-associated suppression of EDD, and was associated with reduced arterial mtROS, oxidative stress, and improved mitochondrial health. MitoQ therapy also reduced aortic stiffness in old mice. A recent small pilot study of older adults (n=20) found that supplementation with MitoQ was well-tolerated, improved endothelial function, and reduced plasma levels of oxidized low-density lipoprotein, a circulating biomarker of oxidative stress. Consistent with the preclinical findings, preliminary mechanistic assessments in subsets of subjects from the pilot study suggested that improved endothelial function with MitoQ was mediated by reduced endothelial cell mtROS production, associated reductions in tonic mtROS-related suppression of EDD, and improved mitochondrial health, linked in part to changes in circulating factors in the serum induced by chronic MitoQ supplementation. Lastly, MitoQ reduced aortic stiffness in older adults who exhibited age-related aortic stiffening at baseline.

The investigators are conducting a randomized, placebo-controlled, double-blind clinical trial to establish oral MitoQ (20 mg/day; MitoQ, Ltd.) for 3 months vs. placebo (n=56/group) for improving endothelial function in older men and women (≥60 years), and determine the mechanisms by which MitoQ improves endothelial function. The investigators will also assess the effect of MitoQ on aortic stiffness.


Condition or disease Intervention/treatment Phase
Aging Dietary Supplement: MitoQ Dietary Supplement: Placebo Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 112 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Other
Official Title: Mitochondrial-targeted Antioxidant Supplementation for Improving Age-related Vascular Dysfunction in Humans
Actual Study Start Date : April 2, 2021
Estimated Primary Completion Date : August 2025
Estimated Study Completion Date : December 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: MitoQ, 20 mg/day
Each MitoQ capsule contains 20 mg of mitoquinol mesylate. Dosage: 20 mg orally per day for 3 months.
 Dietary Supplement: MitoQ
MitoQ is a biochemically modified form of ubiquinol
Other Name: Mitoquinol
Placebo Comparator: Placebo
Matched placebo capsules.
 Dietary Supplement: Placebo
Each placebo capsule contains inert excipient and is identical in appearance


Outcome Measures
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Primary Outcome Measures :
  1. Change from baseline in endothelial function at 3 months [ Time Frame: 3 months ]
    Brachial artery flow-mediated dilation


Secondary Outcome Measures :
  1. Change from baseline in suppression of endothelial function by mitochondrial oxidative stress at 3 months [ Time Frame: 3 months ]
    Change in brachial artery flow-mediated dilation with acute, supratherapeutic MitoQ (160mg)

  2. Change from baseline in aortic stiffness at 3 months [ Time Frame: 3 months ]
    Carotid-femoral pulse wave velocity


Other Outcome Measures:
  1. Change from baseline in serum exposure-induced endothelial cell reactive oxygen species production at 3 months [ Time Frame: 3 months ]
    Endothelial cell whole-cell (CellROX) and mitochondria-specific (MitoSOX) reactive oxygen species levels after treatment with serum from subjects

  2. Change from baseline in endothelial cell markers of oxidative stress and mitochondrial health from baseline at 3 months [ Time Frame: 3 months ]
    Endothelial cell protein expression of nitrotyrosine and Fis1

  3. Change from baseline in carotid artery stiffness at 3 months [ Time Frame: 3 months ]
    Carotid artery beta-stiffness index

  4. Change from baseline in circulating marker of oxidative stress at 3 months [ Time Frame: 3 months ]
    Oxidized LDL levels in blood


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   60 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age 60 years and over
  • Ability to provide informed consent
  • Willing to accept random assignment to condition
  • Body mass index <40 kg/m2
  • Weight stable in the prior 3 months (<2 kg weight change) and willing to remain weight stable throughout the study
  • Free from alcohol dependence or abuse,
  • Mini-mental stage examination score ≥21

Exclusion Criteria:

  • Uncontrolled thyroid disease
  • Regular vigorous aerobic (>6 bouts/week, >60 min/bout at a workload >6 METS)
  • Blood donation within 8 weeks prior to enrolling in the study
Contacts and Locations
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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): NCT04851288


Contacts
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Contact: Morgan Berryman-Maciel 303-735-6410 MitoQstudy@colorado.edu

Locations
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United States, Colorado
University of Colorado Boulder Recruiting
Boulder, Colorado, United States, 80309
Contact: Morgan Berryman-Maciel    303-735-6410    MitoQstudy@colorado.edu   
Contact       seals@colorado.edu   
Principal Investigator: Douglas R Seals, PhD         
Sub-Investigator: Matthew J Rossman, PhD         
Sponsors and Collaborators
University of Colorado, Boulder
National Institute on Aging (NIA)
Investigators
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Principal Investigator: Douglas R Seals University of Colorado, Boulder
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Douglas Seals, PI, University of Colorado, Boulder
ClinicalTrials.gov Identifier: NCT04851288    
Other Study ID Numbers: 20-0502
R01AG066730 ( U.S. NIH Grant/Contract )
First Posted: April 20, 2021    Key Record Dates
Last Update Posted: July 21, 2022
Last Verified: July 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No