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.