HealthyPhase 1NCT00076414
The Effect of Lopinavir/Ritonavir on Endothelial Function
A Phase 1 study testing Acetylcholine and L-NMMA in people with Healthy, run by National Institutes of Health Clinical Center (CC) at 1 site in United States.
Trial summary
This study will examine how the anti-HIV protease inhibitor lopinavir/ritonavir (Kaletra® (Registered Trademark)) affects the function of the endothelium (lining of the arteries). Read more about this study
- Who is it for?
- Any ageHealthy volunteers can take part
- Conditions the study is for
- Healthy
- What is being tested?
- Acetylcholine and L-NMMA
- How many people
- 30 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2004to Sep 2005
- 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 Any age
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Who may be able to join
- Age 18-40.
- Healthy by medical history and physical examination.
- Negative serum pregnancy test for females.
- Females willing to use two forms of birth control including barrier contraception during period of study (lopinavir/ritonavir decreases ethinyl estradiol levels).
- Able to provide informed consent.
- Laboratory values on screening visit within: AST less than 40 units/liter, serum creatinine less than 1.5mg/dl; CPK less than 387, hemoglobin greater than 11.0 g/dL (females) or greater than 12.6 g/dL (males), platelets greater than 154,000/mm(3), total bilirubin less than or equal to 1.5 mg/d
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- Total cholesterol less than 200 mg/dL, LDL cholesterol less than 160 mg/dL, HDL cholesterol greater than 30mg/dL, triglycerides less than 200 mg/dL.
- Non-smoker or not having smoked for the past 6 weeks.
- Negative for HIV by ELISA within 4 weeks of study participation.
Who cannot join
- Concomitant therapy with any prescription, over-the-counter or alternative medication except intermittent use of acetaminophen, non-steroidal anti-inflammatory medications, loperamide or oral contraceptives.
- Inability to obtain venous access for sample collection.
- Presence of diabetes mellitus or fasting blood sugar greater than 126 mg/dL, or abnormal oral glucose tolerance test (2 hour post blood sugar greater than 200 mg/dL).
- Human immunodeficiency virus (HIV) infection.
- Cardiac disease, congestive heart disease, coronary artery disease, angina, carotid stenosis, peripheral vascular disease, cerebrovascular disease, myocardial disease, clinically significant valvular heart disease.
- Any other condition that may interfere with the interpretation of the study results or not be in the best interest of the subject in the opinion of the investigator.
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- Hypertension (systolic blood pressure greater than 140 mmHg or diastolic blood pressure greater than 90 mmHg) on screening visit.
- Observed abnormalities on EKG tracings that are significant in the opinion of the investigator (examples include, AV block, multifocal atrial tachycardia, frequent premature ventricular contractions, etc.).
- Hypotension (systolic blood pressure less than 80 mmHG).
- Pregnant or breastfeeding female.
- Inability to abstain from caffeine use (coffee, tea or soda) or alcohol for 12 hours prior to a blood flow study until the conclusion of the study.
- Heavy alcohol ingestion (4 or more drinks a day) or current substance abuse.
- Hypo or hyper thyroidism.
- Allergy to lidocaine.
- History of hepatitis or other liver disease.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center (CC)
Bethesda, Maryland, 20892
About this study
Official title: The Effect of Lopinavir/Ritonavir on Endothelial Function in Normal Volunteers
This study will examine how the anti-HIV protease inhibitor lopinavir/ritonavir (Kaletra® (Registered Trademark)) affects the function of the endothelium (lining of the arteries). Medications such as protease inhibitors can dramatically change the course of HIV infection in many patients; however, among their side effects is development of abnormal lipid levels resulting in high cholesterol and insulin resistance. These side effects may damage the lining of the arteries that supply blood to the heart, leading to premature coronary artery disease. The study will determine whether lopinavir/ritonavir directly affects endothelial function and whether it alters cholesterol levels, glucose tolerance, and markers of inflammation in people who take the drug for 4 weeks.
Healthy normal volunteers between 18 and 40 years of age may be eligible for this study. Candidates must be HIV-negative and have no history of heart disease, hypertension, or diabetes mellitus. They must not have smoked for at least 6 weeks before entering the study. Volunteers will be screened with a medical history, physical examination, blood tests (including a pregnancy test for women of childbearing potential), and electrocardiogram. In addition, candidates will have an oral glucose tolerance test (see description below).
Read more
Participants will undergo the following procedures:
- Lopinavir/ritonavir: 4 weeks (3 capsules twice a day) beginning study day 1
- Flow-mediated vasodilatation test (study days 0 and 29) - An ultrasound device for measuring the size of the brachial artery (artery in the upper arm) is placed just above the elbow. The size of the artery is measured before and 5 minutes after blood flow to the arm is stopped for 5 minutes, using a blood pressure cuff. The artery is also measured before and after taking nitroglycerin, a medicine that dilates blood vessels. These measurements tell how well the drug treatment works on the cells lining the brachial artery, which is an indicator of coronary artery function. This test takes about 1.5 hours.
- Forearm blood-flow test (study days 1 and 30): Small tubes are inserted into an artery and vein in the forearm at the inside of the elbow. Blood pressure cuffs are placed around the upper arm and wrist, and a strain gauge (a rubber band-like device) is placed around the forearm. When the blood pressure cuffs are inflated, blood flows into the forearm, stretching the strain gauge at a rate proportional to the blood flow. When the devices are in place, a salt water solution is injected in the small tube in the artery. After 20 minutes, small doses of the following drugs are given through the catheter at various intervals: 1) L-NMMA (blocks production of nitric oxide, a substance produced by the blood vessels that causes them to dilate); 2) sodium nitroprusside (dilates blood vessels, increasing blood flow); 3) acetylcholine (lowers blood pressure); and 4) acetylcholine plus L-NMMA. The effect of the different drugs on blood flow in the forearm is measured. The study takes about 2 hours to complete.
- Blood tests (screening and study days 1,15, 30, and 44)
- Electrocardiogram (at screening and on study day 30)
- Oral glucose tolerance test (at screening and on study day 30) - A blood sample is collected. Then, the subject drinks 300 milliliters of a glucose solution (a liquid that contains sugar dissolved in water). Two hours after drinking the solution, blood is drawn again to examine how the body responds to the increase blood sugar levels.
Read the detailed description
With the advent of the highly active antiretroviral (ARV) therapy era, patients with human immunodeficiency virus (HIV) have had significantly decreased mortality and morbidity. Concomitant with more patients chronically taking antiretroviral therapy, there has been an increase in atherogenic lipoprotein profiles (high cholesterol, high triglycerides, low HDL's), insulin resistance, fat redistribution and coronary artery disease. HIV viral replication, anti-retroviral treatment regimens, lipids, glucose intolerance, host immune response or a combination of factors may contribute to the increase in cardiovascular risk factors. HIV positive patients, independent of the effect on lipids, appear to have increased cardiovascular risk. Studies are not entirely consistent, but the most convincing study to date, the D.A.D. study from EURO-SIDA, shows a 27% relative increased rate of myocardial infarction per year of exposure over the first seven years of ART.
Lopinavir-ritonavir is one of the most commonly used antiretroviral therapy. It also produces lipid abnormalities. Thus, an important part of the investigating factors contributing to atherosclerosis would be to determine if this drug can adversely influence endothelial cells in the absence of HIV infection or low CD4 counts. This would suggest that this drug directly or indirectly could predispose to atherosclerosis. Endothelial function is an important contributor to atherosclerosis. Invasive and non-invasive methods to evaluate endothelial cell function have been validated as predictors of coronary artery disease. These techniques have been used at NIH for clinical investigation for many years.
This protocol is designed to determine whether there is a pathologic effect on endothelial function from the lopinavir/ritonavir. By measuring endothelial function in HIV non-infected subjects both before and after four weeks of therapy, we will be able to investigate whether the medications have a direct toxic effect on the endothelium. Collection of metabolic data will allow us to evaluate whether endothelial function occurs in conjunction or separate from lipoprotein and glucose metabolic changes. As ARV options increase, it may be possible to choose specific regimens that may minimize acceleration of cardiovascular risk factors associated with endothelial dysfunction, especially in patients with other cardiovascular risk factors. These findings may help elucidate the pathophysiology of premature cardiovascular disease in HIV positive patients and also plan interventions to minimize endothelial dysfunction and subsequent cardiovascular disease.
- Conditions
- Healthy
- Being tested
- Acetylcholine, L-NMMA
- Keywords
- Endothelial Function, Lopinavir/Ritonavir, HIV, Blood Flow Studies, Flow-Mediated Vasodilatation, Healthy Volunteer, HV
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AcetylcholineDrug
L-NMMADrug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jan 2004 (estimated)
- Study startJan 2004
- Study completionSep 2005
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 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
- Treatment
- Enrolment
- 30 participants
Sponsor and investigators
- Lead sponsor
- National Institutes of Health Clinical Center (CC)
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00076414
- Sponsor's protocol ID
- 040085
- Other IDs
- 04-CC-0085
- Status last verified
- Sep 2005
- First submitted
- 21 Jan 2004
- Last updated
- 4 Mar 2008
- Results posted
- No
Publications
Duong M, Buisson M, Cottin Y, Piroth L, Lhuillier I, Grappin M, Chavanet P, Wolff JE, Portier H. Coronary heart disease associated with the use of human immunodeficiency virus (HIV)-1 protease inhibitors: report of four cases and review. Clin Cardiol. 2001 Oct;24(10):690-4. doi: 10.1002/clc.4960241011.
PubMed 11594416Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet. 1999 Jun 19;353(9170):2093-9. doi: 10.1016/S0140-6736(98)08468-2.
PubMed 10382692Stein JH, Klein MA, Bellehumeur JL, McBride PE, Wiebe DA, Otvos JD, Sosman JM. Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation. 2001 Jul 17;104(3):257-62. doi: 10.1161/01.cir.104.3.257.
PubMed 11457741
Study at a glance
From the registry record, last updated by the sponsor on 4 Mar 2008. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Lopinavir/Ritonavir on Endothelial Function in Normal Volunteers
- ClinicalTrials.gov ID
- NCT00076414
- Acronym / sponsor ID
- 040085
- Conditions
- Healthy
- Keywords
- Endothelial Function, Lopinavir/Ritonavir, HIV, Blood Flow Studies, Flow-Mediated Vasodilatation, Healthy Volunteer, HV
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants
- Lead sponsor
- National Institutes of Health Clinical Center (CC)US National Institutes of Health
- Study start
- Jan 2004
- Study completion
- Sep 2005
- First posted
- 22 Jan 2004 (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 examine how the anti-HIV protease inhibitor lopinavir/ritonavir (Kaletra® (Registered Trademark)) affects the function of the endothelium (lining of the arteries). Medications such as protease inhibitors can dramatically change the course of HIV infection in many patients; however, among their side effects is development of abnormal lipid levels resulting in high cholesterol and insulin resistance. These side effects may damage the lining of the arteries that supply blood to the heart, leading to premature coronary artery disease. The study will determine whether lopinavir/ritonavir directly affects endothelial function and whether it alters cholesterol levels, glucose tolerance, and markers of inflammation in people who take the drug for 4 weeks.
Healthy normal volunteers between 18 and 40 years of age may be eligible for this study. Candidates must be HIV-negative and have no history of heart disease, hypertension, or diabetes mellitus. They must not have smoked for at least 6 weeks before entering the study. Volunteers will be screened with a medical history, physical examination, blood tests (including a pregnancy test for women of childbearing potential), and electrocardiogram. In addition, candidates will have an oral glucose tolerance test (see description below).
Participants will undergo the following procedures:
- Lopinavir/ritonavir: 4 weeks (3 capsules twice a day) beginning study day 1
- Flow-mediated vasodilatation test (study days 0 and 29) - An ultrasound device for measuring the size of the brachial artery (artery in the upper arm) is placed just above the elbow. The size of the artery is measured before and 5 minutes after blood flow to the arm is stopped for 5 minutes, using a blood pressure cuff. The artery is also measured before and after taking nitroglycerin, a medicine that dilates blood vessels. These measurements tell how well the drug treatment works on the cells lining the brachial artery, which is an indicator of coronary artery function. This test takes about 1.5 hours.
- Forearm blood-flow test (study days 1 and 30): Small tubes are inserted into an artery and vein in the forearm at the inside of the elbow. Blood pressure cuffs are placed around the upper arm and wrist, and a strain gauge (a rubber band-like device) is placed around the forearm. When the blood pressure cuffs are inflated, blood flows into the forearm, stretching the strain gauge at a rate proportional to the blood flow. When the devices are in place, a salt water solution is injected in the small tube in the artery. After 20 minutes, small doses of the following drugs are given through the catheter at various intervals: 1) L-NMMA (blocks production of nitric oxide, a substance produced by the blood vessels that causes them to dilate); 2) sodium nitroprusside (dilates blood vessels, increasing blood flow); 3) acetylcholine (lowers blood pressure); and 4) acetylcholine plus L-NMMA. The effect of the different drugs on blood flow in the forearm is measured. The study takes about 2 hours to complete.
- Blood tests (screening and study days 1,15, 30, and 44)
- Electrocardiogram (at screening and on study day 30)
- Oral glucose tolerance test (at screening and on study day 30) - A blood sample is collected. Then, the subject drinks 300 milliliters of a glucose solution (a liquid that contains sugar dissolved in water). Two hours after drinking the solution, blood is drawn again to examine how the body responds to the increase blood sugar levels.
Detailed description
With the advent of the highly active antiretroviral (ARV) therapy era, patients with human immunodeficiency virus (HIV) have had significantly decreased mortality and morbidity. Concomitant with more patients chronically taking antiretroviral therapy, there has been an increase in atherogenic lipoprotein profiles (high cholesterol, high triglycerides, low HDL's), insulin resistance, fat redistribution and coronary artery disease. HIV viral replication, anti-retroviral treatment regimens, lipids, glucose intolerance, host immune response or a combination of factors may contribute to the increase in cardiovascular risk factors. HIV positive patients, independent of the effect on lipids, appear to have increased cardiovascular risk. Studies are not entirely consistent, but the most convincing study to date, the D.A.D. study from EURO-SIDA, shows a 27% relative increased rate of myocardial infarction per year of exposure over the first seven years of ART.
Lopinavir-ritonavir is one of the most commonly used antiretroviral therapy. It also produces lipid abnormalities. Thus, an important part of the investigating factors contributing to atherosclerosis would be to determine if this drug can adversely influence endothelial cells in the absence of HIV infection or low CD4 counts. This would suggest that this drug directly or indirectly could predispose to atherosclerosis. Endothelial function is an important contributor to atherosclerosis. Invasive and non-invasive methods to evaluate endothelial cell function have been validated as predictors of coronary artery disease. These techniques have been used at NIH for clinical investigation for many years.
This protocol is designed to determine whether there is a pathologic effect on endothelial function from the lopinavir/ritonavir. By measuring endothelial function in HIV non-infected subjects both before and after four weeks of therapy, we will be able to investigate whether the medications have a direct toxic effect on the endothelium. Collection of metabolic data will allow us to evaluate whether endothelial function occurs in conjunction or separate from lipoprotein and glucose metabolic changes. As ARV options increase, it may be possible to choose specific regimens that may minimize acceleration of cardiovascular risk factors associated with endothelial dysfunction, especially in patients with other cardiovascular risk factors. These findings may help elucidate the pathophysiology of premature cardiovascular disease in HIV positive patients and also plan interventions to minimize endothelial dysfunction and subsequent cardiovascular disease.
Study design
- Primary purpose
- Treatment
Who may qualify
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (9 listed)
- Age 18-40.
- Healthy by medical history and physical examination.
- Negative serum pregnancy test for females.
- Females willing to use two forms of birth control including barrier contraception during period of study (lopinavir/ritonavir decreases ethinyl estradiol levels).
- Able to provide informed consent.
Key exclusion criteria (15 listed)
- Concomitant therapy with any prescription, over-the-counter or alternative medication except intermittent use of acetaminophen, non-steroidal anti-inflammatory medications, loperamide or oral contraceptives.
- Inability to obtain venous access for sample collection.
- Presence of diabetes mellitus or fasting blood sugar greater than 126 mg/dL, or abnormal oral glucose tolerance test (2 hour post blood sugar greater than 200 mg/dL).
- Human immunodeficiency virus (HIV) infection.
- Cardiac disease, congestive heart disease, coronary artery disease, angina, carotid stenosis, peripheral vascular disease, cerebrovascular disease, myocardial disease, clinically significant valvular heart 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 | Drug | – |
| L-NMMA | Drug | – |
Primary outcome
Not reported in the source record.
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 4 Mar 2008.
- Background: PubMed 11594416Duong M, Buisson M, Cottin Y, Piroth L, Lhuillier I, Grappin M, Chavanet P, Wolff JE, Portier H. Coronary heart disease associated with the use of human immunodeficiency virus (HIV)-1 protease inhibitors: report of four cases and review. Clin Cardiol. 2001 Oct;24(10):690-4. doi: 10.1002/clc.4960241011.
- Background: PubMed 10382692Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet. 1999 Jun 19;353(9170):2093-9. doi: 10.1016/S0140-6736(98)08468-2.
- Background: PubMed 11457741Stein JH, Klein MA, Bellehumeur JL, McBride PE, Wiebe DA, Otvos JD, Sosman JM. Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation. 2001 Jul 17;104(3):257-62. doi: 10.1161/01.cir.104.3.257.
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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 study testing Acetylcholine and L-NMMA in people with Healthy, run by National Institutes of Health Clinical Center (CC) 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 9 inclusion and 15 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 4 Mar 2008. 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.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00076414, 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 4 Mar 2008.