Clinical trial NCT03404843
Conditions: Cardiovascular Diseases
Sponsor: Colorado State University
Start date: 2017-07-14; Completion date: 2018-10-05
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Previous work demonstrates that the red blood cells of older adults do not release a potent vasodilator (ATP) as well as the red blood cells of younger adults. The investigators are targeting a pathway within the red blood cell using fasudil hydrochloride to determine if both the release of ATP from red blood cells and blood flow responses to low oxygen (hypoxia) and exercise in older adults can be improved.

Detailed description:
Participants will initiate contact with the investigators by responding to flyers placed in the community either by phone or email. The first correspondence (phone or email) will provide a brief description of the research and ask a series of screening questions to determine age, height, weight, and any medications participants may be taking as well as the current health status (diagnoses, basic health history, and physical activity level) of participants. If they qualify, a two hour screening visit is scheduled during a time when the participant will be examined by the physician. All participants will undergo informed consent in a face to face private meeting with the research coordinator. Following informed consent, participants will be evaluated by a physician and undergo a treadmill stress test to rule out cardiovascular disease.

During the study, heart rate will be monitored with a 3-lead ECG and blood pressure will be monitored noninvasively with a blood pressure cuff on the finger (finometry). Venous blood will be collected at multiple time points via a catheter inserted into a forearm vein draining skeletal muscle circulation for measurement of blood gases (0.5 mL/sample) and plasma \[ATP\] (2 mL/sample), with less than 100 mL of blood being drawn in total (\~60mL total). Blood flow at rest and in response to hypoxia and exercise will be measured non-invasively using Doppler ultrasound of the brachial artery. Hypoxia trials will be performed by having participants breathe a low oxygen gas mixture via a mouthpiece that is hooked up to gas tanks and an anesthesia monitor to decrease their oxygen saturation to \~80% (similar to hiking a 14er) for 10 minutes. Exercise trials will last for approximately 15 minutes and will involve participants performing graded-intensity rhythmic handgrip exercise by lifting weights (corresponding to a low, moderate, and high workload) using a pulley system. The drug treatment used in this study (fasudil) is being given because it may improve red blood cell ATP release in older adults. This is a double-blinded placebo controlled study, thus participation will occur on two randomized experimental days.

Arms: arm 1: Participants will receive a 100 mL intravenous infusion (in 60 minutes) of 60 mg of fasudil hydrochloride + saline prior to measurements of vascular function and ATP release. arm 2: Participants will receive a 100 mL intravenous infusion (in 60 minutes) of saline (placebo) prior to measurements of vascular function and ATP release.
Interventions: intervention 1: Fasudil Hydrochloride intervention 2: Saline
Intervention descriptions: intervention 1: 10 mg/mL vial of fasudil hydrochloride. 6 mL (60 mg) of fasudil hydrochloride are added to a 100 mL saline bag for delivery to subjects. intervention 2: 100 mL saline bag.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Red Blood Cell ATP Release and Vascular Function in Humans 
 
NCT03404843 
 
May 19, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Fasudil Study Protocol 
 
 
Using a double-blind, placebo-controlled, crossover design, subjects were randomized to 
receive an infusion of either saline (placebo control) or fasudil for their first experimental visit.  
Subjects then received the opposite treatment for their second experimental visit, with at least 
five days and no more than two months between the first and second visit.  All experimental 
measures were performed in the same order for each visit within a subject, with the order of 
hypoxia and graded-intensity rhythmic handgrip exercise trials randomized and counterbalanced 
between subjects.  Arterial stiffness measures (augmentation index and carotid-femoral pulse 
wave velocity) were performed before and after placement of the venous catheter and 60 min 
treatment administration.  For both the hypoxia and exercise trials, resting hemodynamics were 
measured for 2-3 min until a steady-state was observed, after which the physiological stimulus 
was initiated.  The hypoxia trial consisted of 3 min of steady-state hypoxia at an oxygen 
saturation of ~80% as assessed via pulse oximetry on the earlobe (SpO2; plus ~2 min for the 
normoxia to hypoxia transition).  The exercise trial consisted of 4 min at each workload to 
ensure that steady-state hemodynamics were achieved.  Blood samples for plasma [ATP] were 
taken under steady-state conditions at rest, the end of hypoxia, and the end of each exercise 
workload. 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Red Blood Cell ATP Release and Vascular Function in Humans 
 
NCT03404843 
 
May 19, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Fasudil Statistical Analysis Plan 
 
 
All values are reported as mean ± SEM.  All analyses were performed using R (R Core 
Team 2016, R Foundation for Statistical Computing, Vienna, Austria) with the lme4, lmerTest, 
pbkrtest, and lsmeans packages.  Age (young or older), drug (saline or fasudil), condition (rest 
or exercise intensity or hypoxia), and age×drug×condition for three-way repeated measures or 
age×drug for two-way repeated measures ANOVA were treated as fixed effects.  In order to 
account for the crossover design, subject and subject×drug were in included in the model as 
random effects for the three-way repeated measures analyses and subject was included as a 
random effect for the two-way repeated measures analyses.  When an interaction or main effect 
was found, appropriate pairwise comparisons were made and a Tukey test was included when 
necessary.  Comparisons of variables relative to zero were tested using a one-tailed t-test, and 
differences in subject characteristics were tested using a two-tailed t-test.  Comparisons 
between saline and fasudil were performed within age group and comparisons between young 
and old were performed within condition.  Significance was set at P < 0.05.