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.
