Limb IschemiaPhase 1/2NCT00453531
Model System for Transient Forearm Blood Vessel Dysfunction
A Phase 1/2 study testing Limb Ischemia and Acetylcholine in people with Limb Ischemia and Ischemic Preconditioning, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
Trial summary
This study will develop a model system that can be used to test medications for improving the ability of blood vessels to resist damage from diseases such as heart attack and stroke. Read more about this study
- Who is it for?
- Ages 18 to 45 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Limb Ischemia, Ischemic Preconditioning
- What is being tested?
- Limb Ischemia and Acetylcholine
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteUnited States
- Study dates
- 26 Mar 2007to 11 Feb 2009
- Phase
- Phase 1/2
- 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 45 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Subjects must be 18-45 years of age.
- Subjects must be male.
- Subject must be in good health.
- Subject must complete a screening history and physical exam.
- Subjects must provide informed, written consent for participation in this study.
Who cannot join
- Subjects with a history of cardiac, pulmonary, peripheral vascular disease, coagulopathy, or any other disease predisposing to vasculitis or Raynaud's phenomenon.
- Subjects with diabetes or mitochondrial disease.
- Subjects with a history or evidence of present or past hypertension (blood pressure greater than 140/90 mmHg), hypercholesterolemia (LDL cholesterol greater than 160 mg/dL).
- Subjects with abnormal EKG other than sinus bradycardia.
- Subjects who have a history of smoking within three months.
- Subjects with anemia (defined as hemoglobin less than 9 g/dL).
Show all 10Show fewer
- BMI greater than 30
- No volunteer subject will be allowed to take any prescription medication. Vitamin supplements, herbal preparations, nutraceuticals or other alternative therapies must be stopped for two weeks prior to study and aspirin, tylenol and NSAIDs must also be discontinued two weeks prior to study.
- Subjects with a blood pressure of less than 90/60 mmHg or mean arterial pressure (MAP) less than 70 mmHg on the study day will be excluded from the protocol.
- Positive for HIV or Hepatitis B, C.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Pilot Study for the Development of Transient Forearm Endothelial Dysfunction
This study will develop a model system that can be used to test medications for improving the ability of blood vessels to resist damage from diseases such as heart attack and stroke. The endothelium (inner layer of blood vessels) has built-in defense mechanisms to prevent blockage of blood flow, including the ability to stretch the vessel when it senses that blood flow is threatened. People with heart attack risk factors, such as high cholesterol, smoking and diabetes lose this ability. This study will develop a model that can measure the response to a lack of blood flow in the arm and be used to test new medicines to improve blood vessel health.
Healthy males between 18 and 45 years of age who have no history of high blood pressure, high cholesterol, or diabetes and who have not smoked for at least 3 months before entering the study may be eligible to enroll.
Participants lie in an adjustable reclining bed. Small catheters (tubes) are placed in the artery and vein of the forearm of the non-dominant arm at the inside of the elbow. Blood samples are collected from the tubes. Then, pressure cuffs are placed on both wrists and upper arms. A strain gauge (rubber band-type device) is placed around the forearms. The pressure cuffs are inflated and blood flows into the forearm, stretching the strain gauge at a rate proportional to the blood flow. Then, small doses of acetylcholine (a medicine that causes blood vessels to expand) are injected into the artery tube. After 20 minutes, blood flow to the non-dominant arm is blocked by inflating the pressure cuff. The subject squeezes a rubber ball about every 2 seconds for 90 seconds. The cuff is deflated after 15 minutes and blood samples are withdrawn from the tube in the vein. After 15 minutes, the procedure is repeated one more time.
Read the detailed description
Endothelial dysfunction denotes abnormal contractile function of the inner lining of blood vessels. Endothelial dysfunction is associated with hypertension, hypercholesterolemia, atherosclerosis and diabetes and is an independent risk factor for cardiovascular disease. In normal physiology, endothelial cells synthesize and release factors that modulate blood vessel growth, inflammation, homeostasis, and vascular tone. Recently, endothelial dysfunction has been recognized as an early event in ischemia-reperfusion (IR) injury. IR injury causes damage to tissue and is important in many settings including acute coronary artery occlusions and cerebral ischemia. A model to examine the physiology of IR induced endothelial dysfunction and to test pharmacologic agents to prevent IR induced endothelial dysfunction is of paramount importance given the rise in cardiovascular and cerebrovascular disease. Recently in Protocol 06-H-0024, our group found that 20 minutes of ischemic stress causes no absolute endothelial dysfunction to the forearm using venous plethysmography to measure blood flow, despite numerous publications that support this model. We believe that the previously published data are based on a computational error resulting in an erroneous data interpretation (discussed in the introductory section of this proposal). Using NMR spectroscopy in protocol 06-H-0024 we have found that by adding exercise to exhaustion (usually 1 to 2 minutes of concentric exercise) to a 15-minute period of forearm ischemia results in a significantly more robust metabolic stress to the forearm, than 20 minutes of ischemia alone. Given the potential utilization of the restoration of endothelial function as a therapeutic strategy, we propose this pilot study to examine whether 15 minutes of ischemia with exercise to exhaustion (usually 1-2 minutes of concentric exercise) will cause transient IR dependent blunting of endothelial vasodilation as measured by venous plethysmography. In this study, an extension of Protocol 06-H-0024, we hypothesize that in human subjects the addition of concentric exercise to exhaustion, as a means to deplete high energy phosphate stores, will contribute to the development of transient endothelial dysfunction when performed in parallel with a 15-minute forearm ischemic stress. The establishment of a human system to enable the study of transient forearm vessel endothelial dysfunction will enable us to explore therapeutic interventions to protect against endothelial dysfunction.
- Conditions
- Limb Ischemia, Ischemic Preconditioning
- Being tested
- Limb Ischemia, Acetylcholine
- Keywords
- Forearm Ischemia, Endothelial Function, Acetyicholine Vasodilation, Venous Plethysmography, Healthy Volunteer, HV
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Limb IschemiaProcedure or surgery
AcetylcholineDrug
| Study group | Role | What they receive |
|---|---|---|
| Healthy Volunteers | Experimental | Not described Receives: Procedure: Limb Ischemia; Drug: Acetylcholine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in vascular endothelial function.
Secondary outcomes (1)
Assessment of systemic effects of this model system by assess contralateral arm blood flow and by assessing metabolic response to the combined exercise/ischemic stress.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Mar 2007 (estimated)
- Study start26 Mar 2007
- Primary completion11 Feb 2009
- Study completion11 Feb 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Limb IschemiaStudies of the same condition, open and under way.
- More trials run by National Heart, Lung, and Blood Institute (NHLBI)The sponsor's other registered studies.
- 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 1/2
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00453531
- Sponsor's protocol ID
- 070124
- Other IDs
- 07-H-0124
- Status last verified
- Feb 2009
- First submitted
- 28 Mar 2007
- Last updated
- 9 Aug 2022
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Rongen GA, Oyen WJ, Ramakers BP, Riksen NP, Boerman OC, Steinmetz N, Smits P. Annexin A5 scintigraphy of forearm as a novel in vivo model of skeletal muscle preconditioning in humans. Circulation. 2005 Jan 18;111(2):173-8. doi: 10.1161/01.CIR.0000151612.02223.F2. Epub 2004 Dec 27.
PubMed 15623546Kharbanda RK, Peters M, Walton B, Kattenhorn M, Mullen M, Klein N, Vallance P, Deanfield J, MacAllister R. Ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia-reperfusion in humans in vivo. Circulation. 2001 Mar 27;103(12):1624-30. doi: 10.1161/01.cir.103.12.1624.
PubMed 11273988Broadhead MW, Kharbanda RK, Peters MJ, MacAllister RJ. KATP channel activation induces ischemic preconditioning of the endothelium in humans in vivo. Circulation. 2004 Oct 12;110(15):2077-82. doi: 10.1161/01.CIR.0000144304.91010.F0. Epub 2004 Oct 4.
PubMed 15466634
Study at a glance
From the registry record, last updated by the sponsor on 9 Aug 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pilot Study for the Development of Transient Forearm Endothelial Dysfunction
- ClinicalTrials.gov ID
- NCT00453531
- Acronym / sponsor ID
- 070124
- Conditions
- Limb Ischemia, Ischemic Preconditioning
- Keywords
- Forearm Ischemia, Endothelial Function, Acetyicholine Vasodilation, Venous Plethysmography, Healthy Volunteer, HV
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 6 participants (actual)
- Lead sponsor
- National Heart, Lung, and Blood Institute (NHLBI)US National Institutes of Health
- Study start
- 26 Mar 2007
- Primary completion
- 11 Feb 2009 (actual)
- Study completion
- 11 Feb 2009 (actual)
- First posted
- 29 Mar 2007 (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.
This study will develop a model system that can be used to test medications for improving the ability of blood vessels to resist damage from diseases such as heart attack and stroke. The endothelium (inner layer of blood vessels) has built-in defense mechanisms to prevent blockage of blood flow, including the ability to stretch the vessel when it senses that blood flow is threatened. People with heart attack risk factors, such as high cholesterol, smoking and diabetes lose this ability. This study will develop a model that can measure the response to a lack of blood flow in the arm and be used to test new medicines to improve blood vessel health.
Healthy males between 18 and 45 years of age who have no history of high blood pressure, high cholesterol, or diabetes and who have not smoked for at least 3 months before entering the study may be eligible to enroll.
Participants lie in an adjustable reclining bed. Small catheters (tubes) are placed in the artery and vein of the forearm of the non-dominant arm at the inside of the elbow. Blood samples are collected from the tubes. Then, pressure cuffs are placed on both wrists and upper arms. A strain gauge (rubber band-type device) is placed around the forearms. The pressure cuffs are inflated and blood flows into the forearm, stretching the strain gauge at a rate proportional to the blood flow. Then, small doses of acetylcholine (a medicine that causes blood vessels to expand) are injected into the artery tube. After 20 minutes, blood flow to the non-dominant arm is blocked by inflating the pressure cuff. The subject squeezes a rubber ball about every 2 seconds for 90 seconds. The cuff is deflated after 15 minutes and blood samples are withdrawn from the tube in the vein. After 15 minutes, the procedure is repeated one more time.
Detailed description
Endothelial dysfunction denotes abnormal contractile function of the inner lining of blood vessels. Endothelial dysfunction is associated with hypertension, hypercholesterolemia, atherosclerosis and diabetes and is an independent risk factor for cardiovascular disease. In normal physiology, endothelial cells synthesize and release factors that modulate blood vessel growth, inflammation, homeostasis, and vascular tone. Recently, endothelial dysfunction has been recognized as an early event in ischemia-reperfusion (IR) injury. IR injury causes damage to tissue and is important in many settings including acute coronary artery occlusions and cerebral ischemia. A model to examine the physiology of IR induced endothelial dysfunction and to test pharmacologic agents to prevent IR induced endothelial dysfunction is of paramount importance given the rise in cardiovascular and cerebrovascular disease. Recently in Protocol 06-H-0024, our group found that 20 minutes of ischemic stress causes no absolute endothelial dysfunction to the forearm using venous plethysmography to measure blood flow, despite numerous publications that support this model. We believe that the previously published data are based on a computational error resulting in an erroneous data interpretation (discussed in the introductory section of this proposal). Using NMR spectroscopy in protocol 06-H-0024 we have found that by adding exercise to exhaustion (usually 1 to 2 minutes of concentric exercise) to a 15-minute period of forearm ischemia results in a significantly more robust metabolic stress to the forearm, than 20 minutes of ischemia alone. Given the potential utilization of the restoration of endothelial function as a therapeutic strategy, we propose this pilot study to examine whether 15 minutes of ischemia with exercise to exhaustion (usually 1-2 minutes of concentric exercise) will cause transient IR dependent blunting of endothelial vasodilation as measured by venous plethysmography. In this study, an extension of Protocol 06-H-0024, we hypothesize that in human subjects the addition of concentric exercise to exhaustion, as a means to deplete high energy phosphate stores, will contribute to the development of transient endothelial dysfunction when performed in parallel with a 15-minute forearm ischemic stress. The establishment of a human system to enable the study of transient forearm vessel endothelial dysfunction will enable us to explore therapeutic interventions to protect against endothelial dysfunction.
Study design
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Healthy Volunteers | Experimental | Procedure: Limb Ischemia, Drug: Acetylcholine |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- Subjects must be 18-45 years of age.
- Subjects must be male.
- Subject must be in good health.
- Subject must complete a screening history and physical exam.
- Subjects must provide informed, written consent for participation in this study.
Key exclusion criteria (10 listed)
- Subjects with a history of cardiac, pulmonary, peripheral vascular disease, coagulopathy, or any other disease predisposing to vasculitis or Raynaud's phenomenon.
- Subjects with diabetes or mitochondrial disease.
- Subjects with a history or evidence of present or past hypertension (blood pressure greater than 140/90 mmHg), hypercholesterolemia (LDL cholesterol greater than 160 mg/dL).
- Subjects with abnormal EKG other than sinus bradycardia.
- Subjects who have a history of smoking within three months.
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 |
|---|---|---|
| Limb Ischemia | Procedure or surgery | Healthy Volunteers |
| Acetylcholine | Drug | Healthy Volunteers |
Primary outcome
Change in vascular endothelial function.
1 secondary outcome
Assessment of systemic effects of this model system by assess contralateral arm blood flow and by assessing metabolic response to the combined exercise/ischemic stress.
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 9 Aug 2022.
- Background: PubMed 15623546Rongen GA, Oyen WJ, Ramakers BP, Riksen NP, Boerman OC, Steinmetz N, Smits P. Annexin A5 scintigraphy of forearm as a novel in vivo model of skeletal muscle preconditioning in humans. Circulation. 2005 Jan 18;111(2):173-8. doi: 10.1161/01.CIR.0000151612.02223.F2. Epub 2004 Dec 27.
- Background: PubMed 11273988Kharbanda RK, Peters M, Walton B, Kattenhorn M, Mullen M, Klein N, Vallance P, Deanfield J, MacAllister R. Ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia-reperfusion in humans in vivo. Circulation. 2001 Mar 27;103(12):1624-30. doi: 10.1161/01.cir.103.12.1624.
- Background: PubMed 15466634Broadhead MW, Kharbanda RK, Peters MJ, MacAllister RJ. KATP channel activation induces ischemic preconditioning of the endothelium in humans in vivo. Circulation. 2004 Oct 12;110(15):2077-82. doi: 10.1161/01.CIR.0000144304.91010.F0. Epub 2004 Oct 4.
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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.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Limb Ischemia and Acetylcholine in people with Limb Ischemia and Ischemic Preconditioning, run by National Heart, Lung, and Blood Institute (NHLBI) 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 5 inclusion and 10 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 9 Aug 2022. 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 combined 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.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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?
Change in vascular endothelial function.. 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 NCT00453531, which also lists 3 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 9 Aug 2022.