Acetate and Age-associated Arterial Dysfunction

NCT ID: NCT05424263

Last Updated: 2024-03-15

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 66 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-09-29
• Study Completion Date: 2025-09-01

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.

Detailed Description

This is a randomized, double-blind, placebo-controlled, parallel design clinical trial to assess the efficacy of 12 weeks of oral acetate supplementation for improving arterial function in late middle-aged and older (MA/O) adults (50+ years). The primary outcome is brachial artery flow-mediated dilation (FMDba), the gold-standard measure of endothelial function in humans (hypothesis: FMDba will be improved by acetate). The secondary outcome is carotid-femoral pulse wave velocity (CFPWV), the gold-standard measure of large elastic artery stiffness in humans (hypothesis: CFPWV will be reduced by acetate). Various other outcomes will also be measured. All measures will be assessed before and after 12-weeks of supplementation with 4,000 mg/day calcium acetate or placebo.

• Subject Enrollment and Screening: Potential participants will be made aware of the proposed study through various recruitment efforts. Interested participants will contact the research coordinator via phone or email and will be administered a screening form online through the Research Electronic Data Capture (REDCap) system to determine eligibility. REDCap is a secure web-based application designed to support data capture for research studies.
• After hearing a study description and having questions answered by the research coordinator, those eligible and interested in participating in the study will provide written and verbal informed consent, and undergo in-person screening. The investigators plan to consent and screen 88 interested individuals in order to meet the enrollment target of 66 participants (account for an approximately 20% rate of exclusion based on inclusion/exclusion criteria that can only be determined in-person).
• In-person screening will include: review of medical history; physical exam; resting heart rate; resting blood pressure; and a blood draw for metabolic profile, lipid profile, complete blood count, thyroid stimulating hormone, and serum phosphorus. All screening will take place at the Division of Renal Diseases & Hypertension's Clinical Vascular Physiology Core Laboratory, located within the CU Medicine building on the CU Anschutz Medical Campus.
• Participant Randomization: After completing screening, eligible subjects will be randomized to receive either: 1) calcium acetate; or 2) placebo (calcium carbonate), with equal numbers in each group, using a block randomization scheme to balance age group (middle-aged, 50-64 years vs. older, >=65 years) and sex (male vs. female). This trial will be double-blind. Subjects and members of the investigative team involved in the acquisition and analysis of outcomes will be blinded to group assignment.
• Assessment of Study Outcomes: All subjects will undergo testing for all primary, secondary and other outcome measures, as well as assessment of subject characteristics known to effect arterial function, before and after 12-weeks of acetate or placebo supplementation. All measurements will be made after a 12 hour fast from food and caffeine (water allowed) and 24 hours after the last dose of acetate or placebo. All testing will take place in a temperature-controlled laboratory.

Visit 2:

• The Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire will be completed;
• Sleep questionnaire;
• Body composition assessed by Bod Pod and anthropometry.
• Following visit 3, subjects will take home a kit for collecting urine for 24 hours, 3 swabs to collect fecal samples for gut microbiome composition on 3 separate days, a 3-day diet record to monitor nutrient intake, a Actigraph watch to measure physical activity (wear for 3 days), an ambulatory blood pressure monitor (wear for 24-hours; automatic measurements every 20 minutes). Subjects will be provided with written and verbal instructions for proper operation and completion of all these measures. The diet log and monitors will be returned at the next testing visit.

Visit 4:

• Casual blood pressure;
• IV placement and blood sampling;
• Venous endothelial cell collection;
• Measurements of arterial stiffness (carotid-femoral pulse wave velocity, carotid artery compliance);
• Brachial artery FMD with saline (vascular endothelial function);
• Brachial artery FMD after vitamin C infusion (for oxidative stress-mediated suppression of vascular endothelial function).
• Brachial artery dilation to sublingual nitroglycerin (endothelium-independent dilation).
• After completing baseline testing, subjects will begin their assigned intervention (acetate or placebo). Acetate and placebo will be compounded by the CU Anschutz Pharmacy into identical oral liquid solutions, packaged into opaque brown medicine bottles, and dispensed to subjects in 4-week supplies. The subject's name and instructions for dosing and timing will be labeled on the bottles.

Visits 4-5: Check-in visits (after 2, 4, and 8 weeks on intervention)

• Subjects will discuss any issues with tolerability or treatment-emergent adverse events with the research coordinator **The dose of study drug may be reduced slightly, or the timing of when the drug is taken may be adjusted, if subjects report side effects
• Weigh medicine bottle to determine adherence
• Blood draw for serum phosphate levels, standard clinical blood chemistries, and serum acetate **May repeat 1 week later, after adjusting dose, if any results are abnormal
• On weeks 4 and 8, receive next 4-week supply of study drug

After weeks 1, 6, and 10, the coordinator will check-in with subjects about any issues and treatment-emergent adverse events via phone call.

Post-Testing (Visits 7 & 8):

• After completing 12-weeks of acetate or placebo supplementation, subjects will return to the laboratory for reassessment of all outcome and subject characteristic measures made during visits 2 & 3. Post-testing will be identical to the baseline testing procedures and conditions.

Intervention Duration and Study Sample Size: The expected duration for a participant to complete the entire protocol from screening to follow-up testing is 14-16 weeks. Based on our power analysis, 26 participants per group (acetate vs. placebo; 52 total) are needed to detect a significant difference in our primary outcome measure (FMDba). The investigators intend to enroll 66 subjects (33 per group) to allow for an ~20% dropout rate. Based on this, ~2-3 participants will be enrolled each month.

Data Collection and Analysis (including blinding): Collection of outcome measures data will be performed by the PI, Dr. Vienna Brunt, with the assistance of Amy Bazzoni (research coordinator), other professional research staff at the Clinical Vascular Physiology Core Laboratory and/or trainees within Dr. Brunt's lab. IV placement, blood draws and vascular endothelial cell collection will be performed by an experienced research nurse or nurse practitioner. Processing of endothelial cells and serum exposure experiments will be performed by professional research staff, under the direct supervision of the PI. Data analysis will be performed by Dr. Brunt and/or supervised professional/laboratory research staff. Having a single investigator perform all data collection and analysis will remove the potential for inter-investigator variation. Dr. Brunt will remain blinded throughout data collection and analysis.

Conditions

Aging; Vascular Stiffness; Vascular Dilation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Calcium Acetate Oral Solution

Intervention Type: DRUG

Subjects will be supplemented with calcium acetate (4,000 mg/day), as described in the arm/group descriptions, for 12 weeks.

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.

Group Type: PLACEBO_COMPARATOR

Calcium Carbonate Oral Suspension

Intervention Type: DRUG

Subjects will be supplemented with calcium carbonate (2,500 mg/day), as described in the arm/group descriptions, for 12 weeks.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Calcium acetate; Calcium carbonate

Eligibility Criteria

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.

• Minimum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Colorado, Denver

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Vienna Brunt, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Colorado, Denver

Locations

University of Colorado Anschutz Medical Campus

Aurora, Colorado, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Jill Herch, BS

Role: CONTACT

jill.herch@cuanschutz.edu

303-724-5839

Vienna Brunt, PhD

Role: CONTACT

vienna.brunt@cuanschutz.edu

303-724-4898

Facility Contacts

Jill Herch, BS

Role: primary

jill.herch@cuanschutz.edu

303-724-5839

Other Identifiers

22-0473

Identifier Type: -

Identifier Source: org_study_id