Cardiac Allograft VasculopathyNCT01078363
Angiotensin Converting Enzyme (ACE) Inhibition and Cardiac Allograft Vasculopathy
A study testing ramipril in people with Cardiac Allograft Vasculopathy, run by Stanford University at 2 sites in United States.
Trial summary
Cardiac transplantation is the ultimate treatment option for patients with end stage heart failure. Cardiac allograft vasculopathy remains a leading cause of morbidity and mortality after transplantation. Angiotensin converting enzyme inhibitors are used in less than one half of transplant recipients. Read more about this study
- Who is it for?
- Ages 12 years and older
- Conditions the study is for
- Cardiac Allograft Vasculopathy
- What is being tested?
- ramipril
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 96 participants
- Where
- 2 sitesUnited States
- Study dates
- Jun 2009to Apr 2015
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 12 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Heart transplant recipient within the first month of transplant;
- 12 years of age or older;
- Must have a serum creatinine less than 2.0 mg/dl;
- Will provide written informed consent;
- Female patients of childbearing potential must have negative pregnancy test;
- For pediatric patient, parent(s) will provide consent and the child will sign assent.
Who cannot join
- Less than 12 years of age;
- Have more than one solid organ transplant at time of heart transplant;
- Has serum creatinine greater than 2.0 mg/dl;
- Pregnancy.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
VA Palo Alto Health Care System
Palo Alto, California, 94304
Stanford University School of Medicine
Stanford, California, 94305
About this study
Official title: ACE Inhibition and Cardiac Allograft Vasculopathy
Cardiac transplantation is the ultimate treatment option for patients with end stage heart failure.
Cardiac allograft vasculopathy remains a leading cause of morbidity and mortality after transplantation.
Read more
Angiotensin converting enzyme inhibitors are used in less than one half of transplant recipients. Preliminary data suggest that angiotensin converting enzyme inhibitors retard the atherosclerotic plaque development that is the hallmark of cardiac allograft vasculopathy. Moreover, this class of drug appears to increase circulating endothelial progenitor cell number and has anti-inflammatory properties, both of which improve endothelial dysfunction, the key precursor to the development of cardiac allograft vasculopathy.
The objective of this project is to investigate the role of an angiotensin converting enzyme inhibitor, ramipril, in preventing the development of cardiac allograft vasculopathy. During the first month after cardiac transplantation subjects will undergo coronary angiography with intravascular ultrasound measurements of plaque volume in the left anterior descending coronary artery. Using a coronary pressure wire, epicardial artery and microvascular physiology will be assessed. Finally, endothelial function and mediators of endothelial function, including circulating endothelial progenitor cells, will be measured. Subjects will then be randomized in a double blind fashion to either ramipril or placebo. After 1 year, the above assessment will be repeated. The primary endpoint will be the development of cardiac allograft vasculopathy based on intravascular ultrasound-derived parameters. The second aim will be to assess the effect of ramipril on endothelial dysfunction early after transplantation. The final aim is to determine the impact of ramipril on coronary physiology early after transplantation.
Read the detailed description
During the first 4 years of this study, we plan to recruit patients within the first month after OHT. As has become routine at Stanford, study subjects will undergo baseline coronary angiography and IVUS assessment of their left anterior descending coronary artery. Coronary endothelial function will be assessed as well transmyocardial levels of ADMA and other mediators of endothelial function. Blood samples will be obtained for analyzing circulating EPC number and function. Epicardial and microvascular coronary physiology in the left anterior descending coronary artery will be determined by measuring FFR and IMR with a coronary pressure wire(in the adults only). Subjects will then be randomized to either the ACE I(Ramipril), or to placebo, in addition to their usual medications. During years 2 through 5 of this project, study subjects will undergo the above routine invasive assessments at 1 year after OHT. During the 5th year of this project, data analysis and manuscript preparation will occur.
Table 2. Patient Flowchart Time post OHT Event 0-4 Weeks Recruitment and enrollment 4-6 Weeks Baseline angiogram, endothelial function, coronary physiology and IVUS studies 4-6 (at time of baseline)Weeks Baseline blood sampling for circulating EPC studies 4-6 Weeks Randomization to ramipril or placebo to begin one week after baseline studies 5-7 Weeks Titration up of ramipril or placebo Month 3 and month 6: blood sampling for EPC studies. 11-13 Months 1 year angiogram, endothelial function, coronary physiology and IVUS studies 11-13 Months 1 year blood sampling for circulating EPC studies The primary endpoint of the study will be change in plaque volume as determined by IVUS analysis at baseline and 1 year later, between those treated with ramipril compared to those treated with placebo.
Secondary endpoints will include change in circulating EPC number and function, change in ADMA levels,change in coronary endothelium-dependent vasodilation, and change in coronary physiology (FFR and IMR)from baseline to 1 year. Although there are multiple potential mechanisms by which ACE I might reduce CAV, evaluating each of these is beyond the scope of this project. For this reason, we will focus on the likely common final pathway of endothelial dysfunction mediated by dysregulation of ADMA and NOS, as well as changes in EPCs. If this study shows a benefit to ACE I therapy in this population, the goal of future studies will be to determine the exact mechanism by which this occurs and to perform a large, multicenter study comparing ACE I to placebo with hard clinical endpoints. Study visits include two major time points 1) baseline angiogram and IVUS which include recording of angiographic data, lab data, clinical data. 2)assessment at the usual follow up periods post transplant, and these data points will also be collected for research purposes. after base line which usually occurs one month post transplant plus or minus 2 weeks. F/u = q 2 weeks until two months out from tx, then once per month until six months out from TX, then every two months until the patient is 12 months out from TX. Each routine f/u visit includes a physical exam,vital signs, echocardiogram, chest x-ray, a complete metabolic panel ( contains a Creatinine), Complete blood count, immunosuppressant drug blood levels, and a heart biopsy (at the same intervals described above).
- Conditions
- Cardiac Allograft Vasculopathy
- Being tested
- ramipril, Placebo
- Keywords
- Heart Transplantation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ramiprilDrug
Also called Altace
Use of a ACE ( angiotension converting enzyme) inhibitors post heart Transplant for Blood pressure control.
PlaceboDrug
Use of a placebo post heart Transplant for Blood pressure control.
| Study group | Role | What they receive |
|---|---|---|
| ramipril | Active comparator | ramipril, 5mg starting dose to maximum dose of 20mg daily dose for one year. Receives: Drug: ramipril |
| Placebo | Placebo comparator | Sugar pill manufactured to mimic ramipril 5mg starting dose , increasing to 20mg daily for one year. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Cardiac Allograft Vasculopathy(CAV) Defined as Change in IVUS-assessed Plaque Volume From Baseline to One Year
also called transplant coronary artery disease or cardiac transplant vasculopathy defined as coronary artery stenosis(narrowing) ranging from 30 to 70 percent by coronary angiography. Measured in this study as change in IVUS-assessed Plaque Volume from baseline to one year.
Measured: Baseline and 1 Year
Secondary outcomes (5)
Percentage of Participants With ≥20% Coronary Artery Diameter Reduction After Acetylcholine
The percent change in diameter of the left anterior descending artery was measured by quantitative angiography after acetylcholine and compared to baseline angiography. The percentage of participants who had ≥20% coronary artery diameter reduction after acetylcholine at one year is presented.
Measured: At Baseline and 1 Year
ADMA Level at One Year Post Transplant
asymmetric dimethylarginine (ADMA), is an inhibitor of endothelial nitric oxide synthase which is a primary regulator of endothelial function.
Measured: 1 year post Transplant
The Percentage of Endothelial Progenitor Cells ( EPC) in Peripheral Blood in Patients One Year After Transplant
The determination of the percentage of EPC in peripheral blood involved surface staining peripheral blood mononuclear cells (PBMCs) with appropriate fluorescently-labeled antibodies to delineate EPCs from other blood cells, followed by analysis by conventional flow cytometry.
Measured: at one year
Fractional Flow Reserve (FFR) at One Year Post Transplant
FFR is a technique used in coronary catheterization to measure pressure differences across a coronary artery stenosis (narrowing, usually due to atherosclerosis) to determine the likelihood that the stenosis impedes oxygen delivery to the heart muscle (myocardial ischemia). It is defined as the ratio of the distal coronary pressure to the proximal coronary pressure.
Measured: at one year post Transplant
Index of Microcirculatory Resistance at One Year Post Heart Transplant
The index of microcirculatory resistance (IMR) is a pressure-temperature sensor guidewire-based measurement, performed during cardiac catheterization, of the minimum microcirculatory resistance in a specific coronary artery. The IMR provides a quantitative measure of coronary microvasculature status.
Measured: one year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Mar 2010 (estimated)
- Study startJun 2009
- Primary completionApr 2015
- Study completionApr 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Cardiac Allograft VasculopathyStudies of the same condition, open and under way.
- More trials run by Stanford UniversityThe 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 N/A
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 96 participants (actual)
Sponsor and investigators
- Lead sponsor
- Stanford University
- Sponsor type
- University, hospital or other
- Collaborators
- VA Palo Alto Health Care System, Cedars-Sinai Medical Center
- Responsible party
- Principal investigator, William Fearon, Stanford University
- Investigators
- William F Fearon, Principal investigator, Stanford University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01078363
- Sponsor's protocol ID
- SU-12162009-4562
- Other IDs
- 16155 (William Fuller Fearon)
- Status last verified
- Dec 2016
- First submitted
- 26 Feb 2010
- Last updated
- 26 Jan 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Arashi H, Sato T, Kobashigawa J, Luikart H, Kobayashi Y, Okada K, Sinha S, Honda Y, Yeung AC, Khush K, Fearon WF. Long-term clinical outcomes with use of an angiotensin-converting enzyme inhibitor early after heart transplantation. Am Heart J. 2020 Apr;222:30-37. doi: 10.1016/j.ahj.2020.01.003. Epub 2020 Jan 9.
PubMed 32007823Fearon WF, Okada K, Kobashigawa JA, Kobayashi Y, Luikart H, Sana S, Daun T, Chmura SA, Sinha S, Cohen G, Honda Y, Pham M, Lewis DB, Bernstein D, Yeung AC, Valantine HA, Khush K. Angiotensin-Converting Enzyme Inhibition Early After Heart Transplantation. J Am Coll Cardiol. 2017 Jun 13;69(23):2832-2841. doi: 10.1016/j.jacc.2017.03.598.
PubMed 28595700Lee JH, Okada K, Khush K, Kobayashi Y, Sinha S, Luikart H, Valantine H, Yeung AC, Honda Y, Fearon WF. Coronary Endothelial Dysfunction and the Index of Microcirculatory Resistance as a Marker of Subsequent Development of Cardiac Allograft Vasculopathy. Circulation. 2017 Mar 14;135(11):1093-1095. doi: 10.1161/CIRCULATIONAHA.116.025268. No abstract available.
PubMed 28289008
Study at a glance
From the registry record, last updated by the sponsor on 26 Jan 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- ACE Inhibition and Cardiac Allograft Vasculopathy
- ClinicalTrials.gov ID
- NCT01078363
- Acronym / sponsor ID
- SU-12162009-4562
- Conditions
- Cardiac Allograft Vasculopathy
- Keywords
- Heart Transplantation
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 96 participants (actual)
- Lead sponsor
- Stanford UniversityUniversity, hospital or other
- Collaborators
- VA Palo Alto Health Care System, Cedars-Sinai Medical Center
- Study start
- Jun 2009
- Primary completion
- Apr 2015 (actual)
- Study completion
- Apr 2015 (actual)
- First posted
- 2 Mar 2010 (estimated)
- Results
- Posted 27 Jul 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Cardiac transplantation is the ultimate treatment option for patients with end stage heart failure.
Cardiac allograft vasculopathy remains a leading cause of morbidity and mortality after transplantation.
Angiotensin converting enzyme inhibitors are used in less than one half of transplant recipients. Preliminary data suggest that angiotensin converting enzyme inhibitors retard the atherosclerotic plaque development that is the hallmark of cardiac allograft vasculopathy. Moreover, this class of drug appears to increase circulating endothelial progenitor cell number and has anti-inflammatory properties, both of which improve endothelial dysfunction, the key precursor to the development of cardiac allograft vasculopathy.
The objective of this project is to investigate the role of an angiotensin converting enzyme inhibitor, ramipril, in preventing the development of cardiac allograft vasculopathy. During the first month after cardiac transplantation subjects will undergo coronary angiography with intravascular ultrasound measurements of plaque volume in the left anterior descending coronary artery. Using a coronary pressure wire, epicardial artery and microvascular physiology will be assessed. Finally, endothelial function and mediators of endothelial function, including circulating endothelial progenitor cells, will be measured. Subjects will then be randomized in a double blind fashion to either ramipril or placebo. After 1 year, the above assessment will be repeated. The primary endpoint will be the development of cardiac allograft vasculopathy based on intravascular ultrasound-derived parameters. The second aim will be to assess the effect of ramipril on endothelial dysfunction early after transplantation. The final aim is to determine the impact of ramipril on coronary physiology early after transplantation.
Detailed description
During the first 4 years of this study, we plan to recruit patients within the first month after OHT. As has become routine at Stanford, study subjects will undergo baseline coronary angiography and IVUS assessment of their left anterior descending coronary artery. Coronary endothelial function will be assessed as well transmyocardial levels of ADMA and other mediators of endothelial function. Blood samples will be obtained for analyzing circulating EPC number and function. Epicardial and microvascular coronary physiology in the left anterior descending coronary artery will be determined by measuring FFR and IMR with a coronary pressure wire(in the adults only). Subjects will then be randomized to either the ACE I(Ramipril), or to placebo, in addition to their usual medications. During years 2 through 5 of this project, study subjects will undergo the above routine invasive assessments at 1 year after OHT. During the 5th year of this project, data analysis and manuscript preparation will occur.
Table 2. Patient Flowchart Time post OHT Event 0-4 Weeks Recruitment and enrollment 4-6 Weeks Baseline angiogram, endothelial function, coronary physiology and IVUS studies 4-6 (at time of baseline)Weeks Baseline blood sampling for circulating EPC studies 4-6 Weeks Randomization to ramipril or placebo to begin one week after baseline studies 5-7 Weeks Titration up of ramipril or placebo Month 3 and month 6: blood sampling for EPC studies. 11-13 Months 1 year angiogram, endothelial function, coronary physiology and IVUS studies 11-13 Months 1 year blood sampling for circulating EPC studies The primary endpoint of the study will be change in plaque volume as determined by IVUS analysis at baseline and 1 year later, between those treated with ramipril compared to those treated with placebo.
Secondary endpoints will include change in circulating EPC number and function, change in ADMA levels,change in coronary endothelium-dependent vasodilation, and change in coronary physiology (FFR and IMR)from baseline to 1 year. Although there are multiple potential mechanisms by which ACE I might reduce CAV, evaluating each of these is beyond the scope of this project. For this reason, we will focus on the likely common final pathway of endothelial dysfunction mediated by dysregulation of ADMA and NOS, as well as changes in EPCs. If this study shows a benefit to ACE I therapy in this population, the goal of future studies will be to determine the exact mechanism by which this occurs and to perform a large, multicenter study comparing ACE I to placebo with hard clinical endpoints. Study visits include two major time points 1) baseline angiogram and IVUS which include recording of angiographic data, lab data, clinical data. 2)assessment at the usual follow up periods post transplant, and these data points will also be collected for research purposes. after base line which usually occurs one month post transplant plus or minus 2 weeks. F/u = q 2 weeks until two months out from tx, then once per month until six months out from TX, then every two months until the patient is 12 months out from TX. Each routine f/u visit includes a physical exam,vital signs, echocardiogram, chest x-ray, a complete metabolic panel ( contains a Creatinine), Complete blood count, immunosuppressant drug blood levels, and a heart biopsy (at the same intervals described above).
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| ramipril | Active comparator | Drug: ramiprilramipril, 5mg starting dose to maximum dose of 20mg daily dose for one year. |
| Placebo | Placebo comparator | Drug: PlaceboSugar pill manufactured to mimic ramipril 5mg starting dose , increasing to 20mg daily for one year. |
Who may qualify
- Ages
- 12 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (6 listed)
- Heart transplant recipient within the first month of transplant;
- 12 years of age or older;
- Must have a serum creatinine less than 2.0 mg/dl;
- Will provide written informed consent;
- Female patients of childbearing potential must have negative pregnancy test;
Key exclusion criteria (4 listed)
- Less than 12 years of age;
- Have more than one solid organ transplant at time of heart transplant;
- Has serum creatinine greater than 2.0 mg/dl;
- Pregnancy.
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 |
|---|---|---|
| ramiprilAlso: AltaceUse of a ACE ( angiotension converting enzyme) inhibitors post heart Transplant for Blood pressure control. | Drug | ramipril |
| PlaceboUse of a placebo post heart Transplant for Blood pressure control. | Drug | Placebo |
Primary outcome
Cardiac Allograft Vasculopathy(CAV) Defined as Change in IVUS-assessed Plaque Volume From Baseline to One Year
Time frame: Baseline and 1 Year
also called transplant coronary artery disease or cardiac transplant vasculopathy defined as coronary artery stenosis(narrowing) ranging from 30 to 70 percent by coronary angiography. Measured in this study as change in IVUS-assessed Plaque Volume from baseline to one year.
5 secondary outcomes
Percentage of Participants With ≥20% Coronary Artery Diameter Reduction After Acetylcholine
Time frame: At Baseline and 1 Year
ADMA Level at One Year Post Transplant
Time frame: 1 year post Transplant
The Percentage of Endothelial Progenitor Cells ( EPC) in Peripheral Blood in Patients One Year After Transplant
Time frame: at one year
Fractional Flow Reserve (FFR) at One Year Post Transplant
Time frame: at one year post Transplant
Index of Microcirculatory Resistance at One Year Post Heart Transplant
Time frame: one year
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Jan 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 32007823Arashi H, Sato T, Kobashigawa J, Luikart H, Kobayashi Y, Okada K, Sinha S, Honda Y, Yeung AC, Khush K, Fearon WF. Long-term clinical outcomes with use of an angiotensin-converting enzyme inhibitor early after heart transplantation. Am Heart J. 2020 Apr;222:30-37. doi: 10.1016/j.ahj.2020.01.003. Epub 2020 Jan 9.
- Derived from this study: PubMed 28595700Fearon WF, Okada K, Kobashigawa JA, Kobayashi Y, Luikart H, Sana S, Daun T, Chmura SA, Sinha S, Cohen G, Honda Y, Pham M, Lewis DB, Bernstein D, Yeung AC, Valantine HA, Khush K. Angiotensin-Converting Enzyme Inhibition Early After Heart Transplantation. J Am Coll Cardiol. 2017 Jun 13;69(23):2832-2841. doi: 10.1016/j.jacc.2017.03.598.
- Derived from this study: PubMed 28289008Lee JH, Okada K, Khush K, Kobayashi Y, Sinha S, Luikart H, Valantine H, Yeung AC, Honda Y, Fearon WF. Coronary Endothelial Dysfunction and the Index of Microcirculatory Resistance as a Marker of Subsequent Development of Cardiac Allograft Vasculopathy. Circulation. 2017 Mar 14;135(11):1093-1095. doi: 10.1161/CIRCULATIONAHA.116.025268. No abstract available.
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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.
William F Fearon principal investigator
Stanford University
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing ramipril in people with Cardiac Allograft Vasculopathy, run by Stanford University at 2 sites 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 6 inclusion and 4 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 26 Jan 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Jul 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Cardiac Allograft Vasculopathy(CAV) Defined as Change in IVUS-assessed Plaque Volume From Baseline to One Year (time frame: Baseline and 1 Year). 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 NCT01078363, 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 26 Jan 2017.