HealthyPhase 1NCT01137656
Storage Lesion in Banked Blood Due to Disruption of Nitric Oxide (NO) Homeostasis
A Phase 1 study testing Acetylcholine and Blood in people with Healthy, run by Mark Gladwin at 1 site in United States.
Trial summary
The purpose of this study is to explore the impact of aged blood on endothelial function by measuring forearm blood flow during intra-arterial acetylcholine infusion in normal healthy human volunteers after infusion of autologous blood stored for 5-10 days or 35-42 days. Read more about this study
- Who is it for?
- Ages 18 to 50 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy
- What is being tested?
- Acetylcholine and Blood
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 53 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2010to Sep 2013
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Male or female and 18 to 50 years of age.
- Able to read and comprehend the English language
Who cannot join
- Less than 18 or greater than 50 years of age.
- Female < 110 lbs or 50 kg
- Male < 110 lbs or 50 kg
- Hemoglobin <12.5g/dl
- Past medical history or symptoms of blood dyscrasia, diabetes mellitus, hyperlipidemia, obstructive sleep apnea, hypertension, significant cardiac disease and / or known peripheral arterial disease.
- History of cigarette smoking within the last month
Show all 14Show fewer
- Serum creatinine >1.0 mg/dL
- Cognitively impaired subjects, or institutionalized persons and subjects unable or unwilling to complete written informed consent (no proxy consent will be obtained)
- Subjects with a history of blood donation within the last 60 days.
- Subjects who have performed other medical studies involving drug delivery in the last 30 days.
- Subjects with an oxygen saturation value < 92%.
- Any STATIN drug (Fluvastatin, Lovastatin, Pravastatin, Simvastatin, Rosuvastatin) currently or in the 4 weeks prior to the screening day
- Any medication for the treatment of diabetes including oral hypoglycemics or insulin
- lab tests indicating blood dyscrasia, diabetes, hypertension or hypercholesterolemia.Females of childbearing potential who are pregnant or unwilling to undergo pregnancy testing; females with positive pregnancy testing on screening day will be excluded
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, 15213
About this study
The purpose of this study is to explore the impact of aged blood on endothelial function by measuring forearm blood flow during intra-arterial acetylcholine infusion in normal healthy human volunteers after infusion of autologous blood stored for 5-10 days or 35-42 days.
Our hypothesis is that 1) the vasodilatory response to the infusion of acetylcholine will be reduced in the 35-42 day group compared with the 5-10 day group, because of scavenging of the NO released from the endothelium by the hemolytic process in the aged blood, 2) that the infusion of aged stored blood will produce vasoconstriction, measured by reduced forearm blood flow during infusion of the 35-42 day compared with the 5-10 day old blood, and that 3) there will be increases in venous levels of cell free plasma hemoglobin, red cell microparticles, red cell membrane damage, arginase levels and activity, decreased arginine levels, markers of oxidative stress (carbamylated proteins and nitrated tyrosine residues), and increases in plasma in vitro NO consumption during the infusion of 35-42 day old compared to 5-10 day old blood.
Read the detailed description
The increased storage time of transfused blood is associated with an increased risk of cardiovascular events and organ failure. The underlying biological mechanism as to why this happens is not understood. A major abnormality in aged blood is the reduced life span of red blood cells after they are infused. This is associated with rupture of the red blood cells and release of their contents. However, the degree of red blood cell rupture and release of the cell's contents in humans after transfusion has not been well studied. It has been seen that even low levels of red blood cell rupture severely decrease the amount of nitric oxide and other factors that effect how blood vessels function. The purpose of this study is to perform human forearm blood flow studies to evaluate wether there are a sufficient amount these factors released during red blood transfusion to significantly affect how blood vessel function in humans.
This study will enroll normal healthy volunteers between 18 to 50 years of age. 500 ml (1.0 unit) of blood will be collected from subjects who will then return in 5-10 days and be re-infused with the blood 5-10 days after storage.The subjects will return after 25-37 days and be infused with blood 35-42 days after storage. The study will use a tool called strain gauge plethysmography and the drug acetylcholine to measure the effect of fresh (i.e., 5-10 days) versus aged (35-42 days) autologous blood transfusions on forearm blood flow in healthy volunteers.
- Conditions
- Healthy
- Being tested
- Acetylcholine and Blood
- Keywords
- Blood storage, Blood transfusion, Aged blood, Blood Forearm, Storage lesion in blood
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Acetylcholine and BloodDrug
Also called Miochol-e, Miochol
The Acetylcholine solution will be infused intra-arterially at the dosage of 7.5 ug/min for 3 minutes, then 15ug/min for 3 minutes, then 30 ug/min for 3 minutes, after the infusion of normal saline. It will then be infused at 7.5ug/min for 3 minutes, followed by 15ug/min for 3 minutes, followed by 30 ug/min for 3 minutes after the infusion of autologous blood. This will be performed at 5-10 days and 35-42 days of blood storage time.
| Study group | Role | What they receive |
|---|---|---|
| Acetylcholine and Blood | Other | This is single arm study. Acetylcholine and blood is infused in brachial artery of non-dominant arm. Blood flow Receives: Drug: Acetylcholine and Blood |
What is being measured
The primary outcome is the main question the study is designed to answer.
Blood flow response to Acetylcholine.
The primary endpoint will be a comparison of the blood flow responses to the acetylcholine after infusion of 5-10 day old blood compared with the responses after infusion of 35-42 day old blood, each controlled for the opposite arm.
Measured: 5-10 days vs 35-42 days
Secondary outcomes (2)
Change in blood flow response to fresh blood (5-10 days) in comparison to aged blood.
A comparison of the change in blood flow responses at baseline and after infusion of 5-10 day old blood compared with the responses during infusion of 35-42 day old blood, each controlled for the opposite arm.
Measured: 5-10 days vs 35-42 days
Comparison in the levels of various biomarkers of aged blood will be examined in venous blood collected from the antecubital vein during the infusion of 5-10 days versus35-42 days old autologous blood.
Measured: 5-10 days versus 35-42 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Jun 2010 (estimated)
- Study startApr 2010
- Primary completionAug 2013
- Study completionSep 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for HealthyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 53 participants (actual)
Sponsor and investigators
- Lead sponsor
- Mark Gladwin
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Sponsor-investigator, Mark Gladwin, University of Pittsburgh
- Investigators
- Mark T Gladwin, M.D, Principal investigator, University of Pittsburgh and University of Pittsburgh medical center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01137656
- Sponsor's protocol ID
- 686
- Other IDs
- R01HL098032-01
- Status last verified
- Apr 2015
- First submitted
- 3 Jun 2010
- Last updated
- 14 Apr 2015
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Greenwalt TJ, Bryan DJ, Dumaswala UJ. Erythrocyte membrane vesiculation and changes in membrane composition during storage in citrate-phosphate-dextrose-adenine-1. Vox Sang. 1984;47(4):261-70. doi: 10.1111/j.1423-0410.1984.tb01596.x.
PubMed 6485302Rumsby MG, Trotter J, Allan D, Michell RH. Recovery of membrane micro-vesicles from human erythrocytes stored for transfusion: a mechanism for the erythrocyte discocyte-to-spherocyte shape transformation. Biochem Soc Trans. 1977;5(1):126-8. doi: 10.1042/bst0050126. No abstract available.
PubMed 892138Dern RJ, Brewer GJ, Wiorkowski JJ. Studies on the preservation of human blood. II. The relationship of erythrocyte adenosine triphosphate levels and other in vitro measures to red cell storageability. J Lab Clin Med. 1967 Jun;69(6):968-78. No abstract available.
PubMed 6025497Berezina TL, Zaets SB, Morgan C, Spillert CR, Kamiyama M, Spolarics Z, Deitch EA, Machiedo GW. Influence of storage on red blood cell rheological properties. J Surg Res. 2002 Jan;102(1):6-12. doi: 10.1006/jsre.2001.6306.
PubMed 11792145Risbano MG, Kanias T, Triulzi D, Donadee C, Barge S, Badlam J, Jain S, Belanger AM, Kim-Shapiro DB, Gladwin MT. Effects of Aged Stored Autologous Red Blood Cells on Human Endothelial Function. Am J Respir Crit Care Med. 2015 Nov 15;192(10):1223-33. doi: 10.1164/rccm.201501-0145OC.
PubMed 26222884
Study at a glance
From the registry record, last updated by the sponsor on 14 Apr 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Storage Lesion in Banked Blood Due to Disruption of Nitric Oxide (NO) Homeostasis
- ClinicalTrials.gov ID
- NCT01137656
- Acronym / sponsor ID
- 686
- Conditions
- Healthy
- Keywords
- Blood storage, Blood transfusion, Aged blood, Blood Forearm, Storage lesion in blood
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 53 participants (actual)
- Lead sponsor
- Mark GladwinUniversity, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- Apr 2010
- Primary completion
- Aug 2013 (actual)
- Study completion
- Sep 2013 (actual)
- First posted
- 4 Jun 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to explore the impact of aged blood on endothelial function by measuring forearm blood flow during intra-arterial acetylcholine infusion in normal healthy human volunteers after infusion of autologous blood stored for 5-10 days or 35-42 days.
Our hypothesis is that 1) the vasodilatory response to the infusion of acetylcholine will be reduced in the 35-42 day group compared with the 5-10 day group, because of scavenging of the NO released from the endothelium by the hemolytic process in the aged blood, 2) that the infusion of aged stored blood will produce vasoconstriction, measured by reduced forearm blood flow during infusion of the 35-42 day compared with the 5-10 day old blood, and that 3) there will be increases in venous levels of cell free plasma hemoglobin, red cell microparticles, red cell membrane damage, arginase levels and activity, decreased arginine levels, markers of oxidative stress (carbamylated proteins and nitrated tyrosine residues), and increases in plasma in vitro NO consumption during the infusion of 35-42 day old compared to 5-10 day old blood.
Detailed description
The increased storage time of transfused blood is associated with an increased risk of cardiovascular events and organ failure. The underlying biological mechanism as to why this happens is not understood. A major abnormality in aged blood is the reduced life span of red blood cells after they are infused. This is associated with rupture of the red blood cells and release of their contents. However, the degree of red blood cell rupture and release of the cell's contents in humans after transfusion has not been well studied. It has been seen that even low levels of red blood cell rupture severely decrease the amount of nitric oxide and other factors that effect how blood vessels function. The purpose of this study is to perform human forearm blood flow studies to evaluate wether there are a sufficient amount these factors released during red blood transfusion to significantly affect how blood vessel function in humans.
This study will enroll normal healthy volunteers between 18 to 50 years of age. 500 ml (1.0 unit) of blood will be collected from subjects who will then return in 5-10 days and be re-infused with the blood 5-10 days after storage.The subjects will return after 25-37 days and be infused with blood 35-42 days after storage. The study will use a tool called strain gauge plethysmography and the drug acetylcholine to measure the effect of fresh (i.e., 5-10 days) versus aged (35-42 days) autologous blood transfusions on forearm blood flow in healthy volunteers.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Acetylcholine and Blood | Other | Drug: Acetylcholine and BloodThis is single arm study. Acetylcholine and blood is infused in brachial artery of non-dominant arm. Blood flow |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (2 listed)
- Male or female and 18 to 50 years of age.
- Able to read and comprehend the English language
Key exclusion criteria (14 listed)
- Less than 18 or greater than 50 years of age.
- Female < 110 lbs or 50 kg
- Male < 110 lbs or 50 kg
- Hemoglobin <12.5g/dl
- Past medical history or symptoms of blood dyscrasia, diabetes mellitus, hyperlipidemia, obstructive sleep apnea, hypertension, significant cardiac disease and / or known peripheral arterial disease.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Acetylcholine and BloodAlso: Miochol-e, MiocholThe Acetylcholine solution will be infused intra-arterially at the dosage of 7.5 ug/min for 3 minutes, then 15ug/min for 3 minutes, then 30 ug/min for 3 minutes, after the infusion of normal saline. It will then be infused at 7.5ug/min for 3 minutes, followed by 15ug/min for 3 minutes, followed by 30 ug/min for 3 minutes after the infusion of autologous blood. This will be performed at 5-10 days and 35-42 days of blood storage time. | Drug | Acetylcholine and Blood |
Primary outcome
Blood flow response to Acetylcholine.
Time frame: 5-10 days vs 35-42 days
The primary endpoint will be a comparison of the blood flow responses to the acetylcholine after infusion of 5-10 day old blood compared with the responses after infusion of 35-42 day old blood, each controlled for the opposite arm.
2 secondary outcomes
Change in blood flow response to fresh blood (5-10 days) in comparison to aged blood.
Time frame: 5-10 days vs 35-42 days
Comparison in the levels of various biomarkers of aged blood will be examined in venous blood collected from the antecubital vein during the infusion of 5-10 days versus35-42 days old autologous blood.
Time frame: 5-10 days versus 35-42 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Apr 2015.
- Background: PubMed 6485302Greenwalt TJ, Bryan DJ, Dumaswala UJ. Erythrocyte membrane vesiculation and changes in membrane composition during storage in citrate-phosphate-dextrose-adenine-1. Vox Sang. 1984;47(4):261-70. doi: 10.1111/j.1423-0410.1984.tb01596.x.
- Background: PubMed 892138Rumsby MG, Trotter J, Allan D, Michell RH. Recovery of membrane micro-vesicles from human erythrocytes stored for transfusion: a mechanism for the erythrocyte discocyte-to-spherocyte shape transformation. Biochem Soc Trans. 1977;5(1):126-8. doi: 10.1042/bst0050126. No abstract available.
- Background: PubMed 6025497Dern RJ, Brewer GJ, Wiorkowski JJ. Studies on the preservation of human blood. II. The relationship of erythrocyte adenosine triphosphate levels and other in vitro measures to red cell storageability. J Lab Clin Med. 1967 Jun;69(6):968-78. No abstract available.
- Background: PubMed 11792145Berezina TL, Zaets SB, Morgan C, Spillert CR, Kamiyama M, Spolarics Z, Deitch EA, Machiedo GW. Influence of storage on red blood cell rheological properties. J Surg Res. 2002 Jan;102(1):6-12. doi: 10.1006/jsre.2001.6306.
- Derived from this study: PubMed 26222884Risbano MG, Kanias T, Triulzi D, Donadee C, Barge S, Badlam J, Jain S, Belanger AM, Kim-Shapiro DB, Gladwin MT. Effects of Aged Stored Autologous Red Blood Cells on Human Endothelial Function. Am J Respir Crit Care Med. 2015 Nov 15;192(10):1223-33. doi: 10.1164/rccm.201501-0145OC.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mark T Gladwin, M.D principal investigator
University of Pittsburgh and University of Pittsburgh medical center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Acetylcholine and Blood in people with Healthy, run by Mark Gladwin at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Apr 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Blood flow response to Acetylcholine. (time frame: 5-10 days vs 35-42 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01137656, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Apr 2015.