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Angiotensin Converting Enzyme (ACE) Inhibition and Cardiac Allograft Vasculopathy

This study is enrolling participants by invitation only.
Sponsor:
Collaborators:
VA Palo Alto Health Care System
Cedars-Sinai Medical Center
Information provided by (Responsible Party):
William Fearon, Stanford University
ClinicalTrials.gov Identifier:
NCT01078363
First received: February 26, 2010
Last updated: March 26, 2013
Last verified: March 2013
  Purpose

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.


Condition Intervention
Cardiac Allograft Vasculopathy
Drug: Ramipril or placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Prevention
Official Title: ACE Inhibition and Cardiac Allograft Vasculopathy

Resource links provided by NLM:


Further study details as provided by Stanford University:

Primary Outcome Measures:
  • Cardiac Allograft Vasculopathy [ Time Frame: 1 Year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Endothelial Dysfunction [ Time Frame: 1 Year ] [ Designated as safety issue: No ]

Estimated Enrollment: 150
Study Start Date: June 2009
Estimated Study Completion Date: April 2015
Estimated Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: ramipril
ramipril, 5mg starting dose to maximum dose of 20mg daily dose for one year.
Drug: Ramipril or placebo
Placebo Comparator: Placebo
5mg starting dose , increasing to 20mg daily for one year.
Drug: Ramipril or placebo

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).

  Eligibility

Ages Eligible for Study:   12 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01078363

Locations
United States, California
VA Palo Alto Health Care System
Palo Alto, California, United States, 94304
Stanford University School of Medicine
Stanford, California, United States, 94305
Sponsors and Collaborators
Stanford University
VA Palo Alto Health Care System
Cedars-Sinai Medical Center
Investigators
Principal Investigator: William F Fearon Stanford University
  More Information

No publications provided

Responsible Party: William Fearon, Associate Professor of Medicine, Stanford University
ClinicalTrials.gov Identifier: NCT01078363     History of Changes
Other Study ID Numbers: SU-12162009-4562, 16155 (William Fuller Fearon)
Study First Received: February 26, 2010
Last Updated: March 26, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Stanford University:
Heart Transplantation

Additional relevant MeSH terms:
Vascular Diseases
Cardiovascular Diseases
Ramipril
Angiotensin-Converting Enzyme Inhibitors
Antihypertensive Agents
Cardiovascular Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protease Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014