The Short-chain Fatty Acid Acetate for Improving Age-associated Arterial Dysfunction
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 37
- 试验地点
- 2
- 主要终点
- Change in Brachial Artery Flow-Mediated Dilation
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 50 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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;
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Calcium Acetate Oral Solution (Drug)
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.
干预措施: Calcium Carbonate Oral Suspension (Drug)
结局指标
主要结局
Change in Brachial Artery Flow-Mediated Dilation
时间窗: 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.
次要结局
- Change in Carotid-Femoral Pulse Wave Velocity (CFPWV)(12 weeks)
- Change in Casual (seated, resting) systolic blood pressure(12 weeks)