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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Fasudil hydrochloride | Experimental | 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. |
|
| Saline | Placebo Comparator | Participants will receive a 100 mL intravenous infusion (in 60 minutes) of saline (placebo) prior to measurements of vascular function and ATP release. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fasudil Hydrochloride | Drug | 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. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Forearm Blood Flow Responses to Hypoxia After Administration of Intervention | Forearm blood flow measured using Doppler ultrasound before and after 5 minutes of exposure to hypoxia (breathing a mix of low-oxygen gas and room air to achieve oxygen saturations of ~80%). | Within 4 hours after administration of intervention |
| Forearm Blood Flow Responses to Exercise After Administration of Intervention | Forearm blood flow measured using Doppler ultrasound before and during continuous rhythmic handgrip exercise at a low, moderate, and high intensity workload (4 minutes at each workload for 12 minutes in total). | Within 4 hours after administration of intervention |
| Change in ATP Release to Hypoxia After Administration of Intervention | Venous plasma concentrations of ATP measured using a luminometer before and after 5 minutes of exposure to hypoxia (breathing a mix of low-oxygen gas and room air to achieve oxygen saturations of ~80%). | Within 4 hours after administration of intervention |
| Change in ATP Release to Exercise After Administration of Intervention | Venous plasma concentrations of ATP measured using a luminometer before and during continuous rhythmic handgrip exercise at a low, moderate, and high intensity workload (4 minutes at each workload for 12 minutes in total). | Within 4 hours after administration of intervention |
| Measure | Description | Time Frame |
|---|---|---|
| Arterial Stiffness After Administration of Intervention | Arterial stiffness measured non-invasively using a SphygmoCor system after administration of saline (placebo) and fasudil. This is a randomized crossover design study, so participants will receive 1 treatment (saline or fasudil) on their first visit and the other treatment on their second visit. | Immediately following administration of intervention |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Frank Dinenno, PhD | Colorado State University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Colorado State University, Dept. of Health and Exercise Science | Fort Collins | Colorado | 80523 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Fasudil, Then Saline | Participants were randomized to receive a single 100 mL intravenous infusion of 60 mg fasudil hydrocholoride + saline in 60 minutes prior to measurements of vascular function and ATP release. After a washout period of at least 5 days, participants received a single 100 mL intravenous infusion of saline (placebo) in 60 minutes prior to measurements of vascular function and ATP release. |
| FG001 | Saline, Then Fasudil | Participants were randomized to receive a single 100 mL intravenous infusion of saline (placebo) in 60 minutes prior to measurements of vascular function and ATP release. After a washout period of at least 5 days, participants received a single 100 mL intravenous infusion of 60 mg fasudil hydrocholoride + saline in 60 minutes prior to measurements of vascular function and ATP release. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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|
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| ID | Title | Description |
|---|---|---|
| BG000 | Fasudil, Then Saline | Participants were randomized to receive a single 100 mL intravenous infusion of 60 mg fasudil hydrocholoride + saline in 60 minutes prior to measurements of vascular function and ATP release. After a washout period of at least 5 days, participants received a single 100 mL intravenous infusion of saline (placebo) in 60 minutes prior to measurements of vascular function and ATP release. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Forearm Blood Flow Responses to Hypoxia After Administration of Intervention | Forearm blood flow measured using Doppler ultrasound before and after 5 minutes of exposure to hypoxia (breathing a mix of low-oxygen gas and room air to achieve oxygen saturations of ~80%). | All participants who completed both interventions (crossover design) with outcome data collected | Posted | Mean | Standard Error | mL/min | Within 4 hours after administration of intervention |
|
During study visits and 1 month after (as reported by participants)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Young Saline | Participants received a 100 mL intravenous infusion (in 60 minutes) of saline (placebo) prior to outcome measurements |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Frank Dinenno | Colorado State University | 970-491-3203 | frank.dinenno@colostate.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | May 19, 2018 | May 19, 2018 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | May 19, 2018 | May 19, 2018 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| C049347 | fasudil |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
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This is a randomized, double-blind, placebo-controlled, crossover study. Approximately 20 young and 20 older adults will be recruited for participation and randomly assigned to either a placebo (saline) infusion or a fasudil hydrochloride infusion. The dose of fasudil hydrochloride is 60 mg/ 60 min.
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A person not associated with any data collection or data analysis is randomizing the treatment and preparing it in a separate room. All data is collected as visit 1 or visit 2.
| Saline | Other | 100 mL saline bag. |
|
|
| BG001 | Saline, Then Fasudil | Participants were randomized to receive a single 100 mL intravenous infusion of saline (placebo) in 60 minutes prior to measurements of vascular function and ATP release. After a washout period of at least 5 days, participants received a single 100 mL intravenous infusion of 60 mg fasudil hydrocholoride + saline in 60 minutes prior to measurements of vascular function and ATP release. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Body Mass Index | Mean | Standard Deviation | kg/m^2 |
|
| OG002 | Older Saline | Participants received a 100 mL intravenous infusion (in 60 minutes) of saline (placebo) prior to outcome measurements |
| OG003 | Older Fasudil | Participants received a 100 mL intravenous infusion (in 60 minutes) of 60 mg of fasudil hydrochloride + saline prior to outcome measurements |
|
|
|
| Primary | Forearm Blood Flow Responses to Exercise After Administration of Intervention | Forearm blood flow measured using Doppler ultrasound before and during continuous rhythmic handgrip exercise at a low, moderate, and high intensity workload (4 minutes at each workload for 12 minutes in total). | All participants who completed both interventions (crossover design) with outcome data collected | Posted | Mean | Standard Error | mL/min | Within 4 hours after administration of intervention |
|
|
|
|
| Primary | Change in ATP Release to Hypoxia After Administration of Intervention | Venous plasma concentrations of ATP measured using a luminometer before and after 5 minutes of exposure to hypoxia (breathing a mix of low-oxygen gas and room air to achieve oxygen saturations of ~80%). | All participants who completed both interventions (crossover design) with outcome data collected | Posted | Mean | Standard Error | nmol/L | Within 4 hours after administration of intervention |
|
|
|
|
| Primary | Change in ATP Release to Exercise After Administration of Intervention | Venous plasma concentrations of ATP measured using a luminometer before and during continuous rhythmic handgrip exercise at a low, moderate, and high intensity workload (4 minutes at each workload for 12 minutes in total). | All participants who completed both interventions (crossover design) with outcome data collected | Posted | Mean | Standard Error | nmol/L | Within 4 hours after administration of intervention |
|
|
|
|
| Secondary | Arterial Stiffness After Administration of Intervention | Arterial stiffness measured non-invasively using a SphygmoCor system after administration of saline (placebo) and fasudil. This is a randomized crossover design study, so participants will receive 1 treatment (saline or fasudil) on their first visit and the other treatment on their second visit. | All participants who completed both interventions (crossover design) with outcome data collected | Posted | Mean | Standard Error | m/s | Immediately following administration of intervention |
|
|
|
|
| 0 |
| 12 |
| 0 |
| 12 |
| 0 |
| 12 |
| EG001 | Young Fasudil | Participants received a 100 mL intravenous infusion (in 60 minutes) of 60 mg of fasudil hydrochloride + saline prior to outcome measurements | 0 | 12 | 0 | 12 | 0 | 12 |
| EG002 | Older Saline | Participants received a 100 mL intravenous infusion (in 60 minutes) of saline (placebo) prior to outcome measurements | 0 | 13 | 0 | 13 | 0 | 13 |
| EG003 | Older Fasudil | Participants received a 100 mL intravenous infusion (in 60 minutes) of 60 mg of fasudil hydrochloride + saline prior to outcome measurements | 0 | 13 | 0 | 13 | 0 | 13 |
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| D017670 |
| Sodium Compounds |
| <0.05 |
| Other |
| 0.37 |
| Other |
| 0.30 |
| Other |
| 0.05 |
| Other |