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Acetate and Age-associated Arterial Dysfunction

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ClinicalTrials.gov Identifier: NCT05424263
Recruitment Status : Recruiting
First Posted : June 21, 2022
Last Update Posted : October 12, 2022
Information provided by (Responsible Party):
University of Colorado, Denver

Brief Summary:

Cardiovascular diseases are the leading cause of morbidity and mortality and contribute most to healthcare costs in the U.S. Age is the strongest cardiovascular disease risk factor, with >90% of all deaths from cardiovascular disease occurring in adults >50 years old. The age-associated increased risk of cardiovascular disease is due, in large part, to the development of arterial dysfunction, including endothelial dysfunction and stiffening of the large elastic arteries. Therefore, novel, effective interventions that improve arterial function will have a large public health impact by decreasing the risk of cardiovascular diseases.

The short-chain fatty acid acetate is endogenously produced by the gut microbiome from fermentation of dietary soluble fiber. High-fiber diets reduce risk of cardiovascular diseases, but unfortunately, a low percentage of Americans meet guidelines for adequate dietary fiber intake and, despite nationwide efforts to improve this, trends in fiber intake have not improved over the last 20+ years. Thus, directly supplementing acetate may be a more practical and feasible intervention for effectively improving arterial function in older adults and reducing the risk of cardiovascular diseases.

The investigators will conduct a study to determine the efficacy of 12 weeks of oral supplementation with acetate for improving arterial function in late middle-aged and older (50+ years) adults. They will also assess the safety and tolerability of acetate supplementation in these adults and perform innovative mechanistic analyses to determine how acetate supplementation improves arterial function. The investigators hypothesize that oral acetate supplementation will improve arterial function by decreasing oxidative stress and increasing nitric oxide bioavailability, and also hypothesize that acetate supplementation will be safe and promote high rates of adherence.

Condition or disease Intervention/treatment Phase
Aging Vascular Stiffness Vascular Dilation Drug: Calcium Acetate Oral Solution Drug: Calcium Carbonate Oral Suspension Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 66 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: This study is double-blind. The study drug and placebo will be compounded into visually-identical oral liquid solutions and packaged in identical opaque brown medicine bottles. Only the pharmacy and biostatistician conducting the randomization will know which group subjects are assigned to.
Primary Purpose: Treatment
Official Title: The Short-chain Fatty Acid Acetate for Improving Age-associated Arterial Dysfunction
Actual Study Start Date : September 29, 2022
Estimated Primary Completion Date : June 1, 2025
Estimated Study Completion Date : June 1, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Calcium

Arm Intervention/treatment
Experimental: Acetate
Subjects will be orally supplemented with calcium acetate for 12 weeks. Subjects will be instructed to take a volume of the oral liquid solution that contains 1,334 mg of calcium acetate 3x per day with meals, for a total dose of 4,000 mg/day. Calcium acetate will be compounded by the CU Anschutz Medical Campus Research Pharmacy and dispensed to subjects in 4-week supplies.
Drug: Calcium Acetate Oral Solution
Subjects will be supplemented with calcium acetate (4,000 mg/day), as described in the arm/group descriptions, for 12 weeks.
Other Name: Calcium acetate

Placebo Comparator: Placebo
Subjects will be orally supplemented with calcium carbonate for 12 weeks. This placebo has been selected to match any potential effects of calcium and phosphate binding of the calcium acetate, i.e., we will isolate the effects of acetate. Subjects will be instructed to take a volume of the oral liquid solution equal to that of the calcium acetate group 3x per day with meals. To match the amount of elemental calcium between calcium acetate and calcium carbonate, this dose of calcium carbonate will contain 833 mg of calcium carbonate, for a total dose of 2,500 mg/day. Calcium carbonate will be compounded by the CU Anschutz Medical Campus Research Pharmacy, visually identical to calcium acetate including the packaging, and dispensed to subjects in 4-week supplies.
Drug: Calcium Carbonate Oral Suspension
Subjects will be supplemented with calcium carbonate (2,500 mg/day), as described in the arm/group descriptions, for 12 weeks.
Other Name: Calcium carbonate

Primary Outcome Measures :
  1. Change in Brachial Artery Flow-Mediated Dilation [ Time Frame: 12 weeks ]
    Nitric oxide-mediated endothelium dependent dilation (vascular endothelial function) will be assessed at baseline and end-intervention by flow-mediated dilation of the brachial artery determined using high-resolution ultrasonography (Canon Xario 200) and analyzed with a commercially available software package (Vascular Analysis Tools, Medical Imaging Applications, LLC). Brachial artery flow-mediated dilation will be assessed by measuring brachial artery diameter and forearm blood flow at baseline and for 2 minutes following reactive hyperemia induced by 5 minutes of forearm blood flow occlusion (upper forearm cuff placement). Data will be expressed as a percent change in arterial diameter from pre-cuff inflation diameter, and then as a change in this % from baseline to end-intervention.

Secondary Outcome Measures :
  1. Change in Carotid-Femoral Pulse Wave Velocity (CFPWV) [ Time Frame: 12 weeks ]
    A transcutaneous tonometer (Noninvasive Hemodynamics Workstation, Cardiovascular Engineering Inc.) will be positioned at the carotid and femoral arteries, and CFPWV will be calculated as the mean distance/time between the foot of the carotid and femoral arterial waveforms calculated over >30 heart cycles. Data will be expressed as m/s. Change in CFPWV from baseline to end-intervention will be determined.

  2. Change in Casual (seated, resting) systolic blood pressure [ Time Frame: 12 weeks ]
    Casual (resting, seated) measures of blood pressure (mmHg) will be measured according to American Heart Association/American College of Cardiology guidelines. Briefly, blood pressure will be measured in triplicate over the brachial artery of the non-dominant arm after 5 minutes of quiet rest, with 1 minute of recovery between each measure. Subjects will be seated quietly with their back supported, feet flat on the floor, and arm at heart level. Casual systolic blood pressure (SBP) will be defined as the average of the three measures. Change in casual SBP from baseline to end-intervention will be determined.

Other Outcome Measures:
  1. Change in 24-hour ambulatory blood pressure [ Time Frame: 12 weeks ]
    Brachial artery blood pressure (mmHg) will be measured automatically every 20 minutes for a 24-hour period by an ambulatory blood pressure monitor (Oscar 2, SunTech Medical) validated according to British Hypertension Society Standards. Participants will be outfitted with the ambulatory blood pressure monitor by a trained investigator. The blood pressure cuff will be placed securely on the participant's non-dominant arm. Participants will be given written and verbal instructions on monitor operation. Ambulatory blood pressure recordings will be analyzed for mean 24-hour (averaged over the entire 24-hour period) SBP, and the change in 24-hour SBP from baseline to end-intervention will be determined.

  2. Incidence of enrolled subjects dropping out of the study due to adverse events [ Time Frame: 12 weeks ]
    The rate at which enrolled subjects drop out of the study due to adverse events, as an indicator of the degree to which overt adverse effects can be tolerated by our subjects.

  3. % of prescribed amount of drug that is consumed [ Time Frame: 12 weeks ]
    Adherence to the intervention will be assessed by determining the average % of prescribed study drug that is actually consumed by subjects across the intervention.

  4. Change in serum acetate [ Time Frame: 12 weeks ]
    Venous blood samples will be analyzed for concentrations of acetate using commercially available kit.

  5. Change in gut microbiome composition [ Time Frame: 12 weeks ]
    16S rRNA genes isolated from fecal bacterial DNA (3 fecal swabs) will be amplified at the V4 region and subjected to multiplex Illumina sequencing. Raw sequences will be processed using the Qiita deblur pipeline and assigned taxonomic classification using the feature-classifier/classify-sklearn plugin in QIIME2. Differential abundance across time into the interventions and across groups (acetate vs. placebo) will be analyzed via ANCOM.

  6. Change in Suppression of Brachial Artery Flow-Mediated Dilation by Oxidative Stress [ Time Frame: Baseline, 12 weeks ]
    Suppression of FMDba will be determined as the difference in FMDba (%change units) following 20 minutes of intravenous infusion with vitamin C (0.06 g/kg fat-free mass) vs. following 20 minutes of intravenous infusion with saline. The change in this outcome will be determined from baseline to end-intervention.

  7. Change in Endothelial Cell Markers of Oxidative Stress [ Time Frame: 12 weeks ]
    Endothelial cells will be obtained from an antecubital vein via clinical endovascular biopsy--2 sterile 0.025-inch J-wires will briefly advanced through an intravenous catheter. Cells will be recovered by centrifugation, fixed with formaldehyde, and slides will be prepared and frozen. Slides will be stained for the primary antibody of interest and a complementary fluorescent secondary Alexafluor 647 antibody (Invitrogen). Slides will also be stained for the extracellular domain of vascular endothelial cadherin (Abcam) for positive identification of endothelial phenotype and DAPI for nuclear integrity. Images will be digitally captured and analyzed using Metamorph Software (Universal Imaging Corp). Values will be reported as ratios of subject endothelial cell protein expression to human umbilical vein endothelial cell control cells protein expression. We will determine the change in expression of proteins related to oxidative stress (e.g., nitrotyrosine and NADPH oxidase).

Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Able to provide informed consent;
  • Age 50+ years;
  • Serum phosphorus levels >= 2.5 mg/dl at screening;
  • Habitual dietary fiber intake <30 g/day for men or <21 g/day for women, based on Block Fiber Screener conducted at screening;
  • Weight-stable in the 3 months prior to enrollment (self-report);
  • Willing to abstain from dietary supplements for 48 hours and from alcohol, tobacco, and cannabis products for 24 hours before all visits;

Exclusion Criteria:

  • History of current serious, chronic clinical disease, e.g., cardiovascular disease, diabetes, liver disease, Alzheimer's disease and related dementias, cancer;
  • Major changes in health in the past 3 months, e.g., hospitalizations, major surgeries, significant changes in medications;
  • Currently taking calcium acetate or any other calcium supplementation;
  • Screening FMDba > 8%;
  • Body mass index > 40 kg/m^2 at screening;
  • Regular vigorous/aerobic endurance >4 bouts/week for >30 min/bout at a workload of >6 METS;
  • Any apparent dependence on or abuse of alcohol, tobacco, and cannabis products;
  • Pregnancy, breast-feeding, or plans to become pregnant during the duration of the study;
  • Any finding on the medical history, physical exam, or standard clinical blood labs that, in the opinion of the physician of record, would put the subject at increased risk with calcium supplementation.

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): NCT05424263

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Contact: Amy Bazzoni, BA 303-724-5839 amy.bazzoni@cuanschutz.edu
Contact: Vienna Brunt, PhD 303-724-4898 vienna.brunt@cuanschutz.edu

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United States, Colorado
University of Colorado Anschutz Medical Campus Recruiting
Aurora, Colorado, United States, 80045
Contact: Amy Bazzoni, BA    303-724-5839    amy.bazzoni@cuanschutz.edu   
Principal Investigator: Vienna E Brunt, PhD         
Sponsors and Collaborators
University of Colorado, Denver
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Principal Investigator: Vienna Brunt, PhD University of Colorado - Anschutz Medical Campus
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Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT05424263    
Other Study ID Numbers: 22-0473
First Posted: June 21, 2022    Key Record Dates
Last Update Posted: October 12, 2022
Last Verified: October 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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.: Yes
Keywords provided by University of Colorado, Denver:
Short-chain fatty acids
Gut microbiome
Arterial function
Additional relevant MeSH terms:
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Dilatation, Pathologic
Pathological Conditions, Anatomical
Calcium, Dietary
Calcium Carbonate
Calcium acetate
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Bone Density Conservation Agents
Molecular Mechanisms of Pharmacological Action
Gastrointestinal Agents
Chelating Agents
Sequestering Agents