Ignite Creation Date:
2025-12-24 @ 1:30 PM
Ignite Modification Date:
2025-12-29 @ 1:27 AM
Study NCT ID:
NCT01305395
Status:
WITHDRAWN
Last Update Posted:
2017-01-24
First Post:
2011-02-25
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Strategies To Prevent Cardiac Allograft Vasculopathy Related Events in Heart Transplant Recipients
Sponsor:
Organization:
Raw JSON
{'hasResults': False, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'interventionBrowseModule': {'meshes': [{'id': 'D020123', 'term': 'Sirolimus'}], 'ancestors': [{'id': 'D018942', 'term': 'Macrolides'}, {'id': 'D007783', 'term': 'Lactones'}, {'id': 'D009930', 'term': 'Organic Chemicals'}]}}, 'protocolSection': {'designModule': {'phases': ['NA'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'RANDOMIZED', 'maskingInfo': {'masking': 'NONE'}, 'primaryPurpose': 'PREVENTION', 'interventionModel': 'PARALLEL'}, 'enrollmentInfo': {'type': 'ACTUAL', 'count': 0}}, 'statusModule': {'whyStopped': 'Due in part, to reduced transplant volume and enrollment has been difficult.', 'overallStatus': 'WITHDRAWN', 'startDateStruct': {'date': '2010-11'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2017-01', 'completionDateStruct': {'date': '2015-01', 'type': 'ACTUAL'}, 'lastUpdateSubmitDate': '2017-01-23', 'studyFirstSubmitDate': '2011-02-25', 'studyFirstSubmitQcDate': '2011-02-25', 'lastUpdatePostDateStruct': {'date': '2017-01-24', 'type': 'ESTIMATED'}, 'studyFirstPostDateStruct': {'date': '2011-02-28', 'type': 'ESTIMATED'}, 'primaryCompletionDateStruct': {'date': '2015-01', 'type': 'ACTUAL'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': '1. Change in maximal intimal thickness', 'timeFrame': '1, 2, 3 and 4 years'}], 'secondaryOutcomes': [{'measure': 'Mean maximal intima thickness', 'timeFrame': '1, 2, 3, and 4 years'}, {'measure': 'Percent atheroma volume', 'timeFrame': '1,2,3 and 4 years'}, {'measure': 'Death from CAV, death from any cause, myocardial infarction, need for percutaneous coronary intervention (PCI), number of hospitalizations, infection rates, evidence of restrictive physiology, arrhythmic event related to CAV or pulmonary hypertension', 'timeFrame': 'at 4 years.'}, {'measure': 'Change in small artery elasticity', 'timeFrame': 'At 1, 2, 3, and 4 years'}, {'measure': 'Change in endothelial progenitor cell count', 'timeFrame': 'At 1 and 2 years'}, {'measure': 'Change in biomarkers', 'timeFrame': 'At 1 and 2 years'}]}, 'oversightModule': {'oversightHasDmc': True}, 'conditionsModule': {'keywords': ['Cardiac Allograft Vasculopathy in Heart Transplant'], 'conditions': ['Cardiac Allograft Vasculopathy']}, 'referencesModule': {'references': [{'pmid': '19782285', 'type': 'BACKGROUND', 'citation': 'Christie JD, Edwards LB, Aurora P, Dobbels F, Kirk R, Rahmel AO, Stehlik J, Taylor DO, Kucheryavaya AY, Hertz MI. The Registry of the International Society for Heart and Lung Transplantation: Twenty-sixth Official Adult Lung and Heart-Lung Transplantation Report-2009. J Heart Lung Transplant. 2009 Oct;28(10):1031-49. doi: 10.1016/j.healun.2009.08.004. No abstract available.'}, {'pmid': '17038650', 'type': 'BACKGROUND', 'citation': 'Rahmani M, Cruz RP, Granville DJ, McManus BM. Allograft vasculopathy versus atherosclerosis. Circ Res. 2006 Oct 13;99(8):801-15. doi: 10.1161/01.RES.0000246086.93555.f3.'}, {'pmid': '9323100', 'type': 'BACKGROUND', 'citation': 'Weis M, von Scheidt W. Cardiac allograft vasculopathy: a review. Circulation. 1997 Sep 16;96(6):2069-77. doi: 10.1161/01.cir.96.6.2069.'}, {'pmid': '1991903', 'type': 'BACKGROUND', 'citation': 'Johnson DE, Alderman EL, Schroeder JS, Gao SZ, Hunt S, DeCampli WM, Stinson E, Billingham M. Transplant coronary artery disease: histopathologic correlations with angiographic morphology. J Am Coll Cardiol. 1991 Feb;17(2):449-57. doi: 10.1016/s0735-1097(10)80114-7.'}, {'pmid': '7798497', 'type': 'BACKGROUND', 'citation': 'Rickenbacher PR, Pinto FJ, Chenzbraun A, Botas J, Lewis NP, Alderman EL, Valantine HA, Hunt SA, Schroeder JS, Popp RL, et al. Incidence and severity of transplant coronary artery disease early and up to 15 years after transplantation as detected by intravascular ultrasound. J Am Coll Cardiol. 1995 Jan;25(1):171-7. doi: 10.1016/0735-1097(94)00323-i.'}, {'pmid': '12531412', 'type': 'BACKGROUND', 'citation': 'Costello JM, Wax DF, Binns HJ, Backer CL, Mavroudis C, Pahl E. A comparison of intravascular ultrasound with coronary angiography for evaluation of transplant coronary disease in pediatric heart transplant recipients. J Heart Lung Transplant. 2003 Jan;22(1):44-9. doi: 10.1016/s1053-2498(02)00484-9.'}, {'pmid': '12973108', 'type': 'BACKGROUND', 'citation': 'Sharples LD, Jackson CH, Parameshwar J, Wallwork J, Large SR. Diagnostic accuracy of coronary angiography and risk factors for post-heart-transplant cardiac allograft vasculopathy. Transplantation. 2003 Aug 27;76(4):679-82. doi: 10.1097/01.TP.0000071200.37399.1D.'}, {'pmid': '15862430', 'type': 'BACKGROUND', 'citation': 'Kobashigawa JA, Tobis JM, Starling RC, Tuzcu EM, Smith AL, Valantine HA, Yeung AC, Mehra MR, Anzai H, Oeser BT, Abeywickrama KH, Murphy J, Cretin N. Multicenter intravascular ultrasound validation study among heart transplant recipients: outcomes after five years. J Am Coll Cardiol. 2005 May 3;45(9):1532-7. doi: 10.1016/j.jacc.2005.02.035.'}, {'pmid': '15862431', 'type': 'BACKGROUND', 'citation': 'Tuzcu EM, Kapadia SR, Sachar R, Ziada KM, Crowe TD, Feng J, Magyar WA, Hobbs RE, Starling RC, Young JB, McCarthy P, Nissen SE. Intravascular ultrasound evidence of angiographically silent progression in coronary atherosclerosis predicts long-term morbidity and mortality after cardiac transplantation. J Am Coll Cardiol. 2005 May 3;45(9):1538-42. doi: 10.1016/j.jacc.2004.12.076.'}, {'pmid': '12742978', 'type': 'BACKGROUND', 'citation': 'Mancini D, Pinney S, Burkhoff D, LaManca J, Itescu S, Burke E, Edwards N, Oz M, Marks AR. Use of rapamycin slows progression of cardiac transplantation vasculopathy. Circulation. 2003 Jul 8;108(1):48-53. doi: 10.1161/01.CIR.0000070421.38604.2B. Epub 2003 May 12.'}, {'pmid': '15262845', 'type': 'BACKGROUND', 'citation': "Keogh A, Richardson M, Ruygrok P, Spratt P, Galbraith A, O'Driscoll G, Macdonald P, Esmore D, Muller D, Faddy S. Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial. Circulation. 2004 Oct 26;110(17):2694-700. doi: 10.1161/01.CIR.0000136812.90177.94. Epub 2004 Jul 19."}, {'pmid': '18025531', 'type': 'BACKGROUND', 'citation': 'Raichlin E, Bae JH, Khalpey Z, Edwards BS, Kremers WK, Clavell AL, Rodeheffer RJ, Frantz RP, Rihal C, Lerman A, Kushwaha SS. Conversion to sirolimus as primary immunosuppression attenuates the progression of allograft vasculopathy after cardiac transplantation. Circulation. 2007 Dec 4;116(23):2726-33. doi: 10.1161/CIRCULATIONAHA.107.692996. Epub 2007 Nov 19.'}, {'pmid': '19383734', 'type': 'BACKGROUND', 'citation': 'Raichlin E, Prasad A, Kremers WK, Edwards BS, Rihal CS, Lerman A, Kushwaha SS. Sirolimus as primary immunosuppression is associated with improved coronary vasomotor function compared with calcineurin inhibitors in stable cardiac transplant recipients. Eur Heart J. 2009 Jun;30(11):1356-63. doi: 10.1093/eurheartj/ehp123. Epub 2009 Apr 21.'}]}, 'descriptionModule': {'briefSummary': '1. Early initiation of sirolimus will prevent or delay the development of intimal thickening and subsequent graft failure.\n2. Treatment guided by the development of cardiac allograft vasculopathy (CAV) on intravascular ultrasound (IVUS) will be more effective in delaying progression of CAV compared to treatment guided by angiography.\n3. Prevention of the development and progression of intimal thickness on IVUS will prevent the development of heart failure, graft dysfunction, and cardiovascular death related to CAV.\n4. Small artery elasticity predicts progression of cardiac allograft vasculopathy and is modified by sirolimus\n5. Patients who have no progression of CAV will have favorable improvement in biomarkers and endothelial cells compared to patients who have progression of CAV', 'detailedDescription': 'Proliferation signal inhibitors (PSIs), sirolimus and everolimus, have been demonstrated to be effective immunosuppressants and delay the progression of cardiac allograft vasculopathy. To date, there are no prospective studies designed to evaluate the potential use of PSIs as a primary immunosuppressant in the prevention of cardiac allograft vasculopathy. The goals of our study are to compare primary vs. secondary preventive strategies and to evaluate the role of intravascular ultrasound compared to coronary angiogram in diagnosing CAV and preventing CAV-related events. The specific aims of the study are:\n\n1. To evaluate the effect of primary vs. secondary initiation of sirolimus on the development of significant coronary artery (\\> 70% angiographic stenosis, Mean intimal thickness (MIT) 0.5mm or greater, IVUS calculated coronary cross sectional area of \\< 4mm2 / \\<6mm2 for mid LAD/Left Maim (LM), \\< 0.75 fractional flow reserve (FFR) lesion associated with a positive stress test), change in global left ventricle (LV) function, incidence of rejection episodes, and hospitalizations at 1, 2, 3, and 4 years.\n2. To determine the effect of IVUS-guided initiation of sirolimus on short-term and long-term outcomes vs. angiogram-guided initiation of sirolimus\n3. To determine whether prevention of progression of CAV diagnosed by IVUS prevents graft dysfunction or death related to CAV or heart failure.\n4. To assess the correlation between peripheral small artery elasticity, peripheral biomarkers, and endothelial cells, and development of cardiac allograft vasculopathy in order to develop a strategy for determining risk of progression and monitoring treatment.\n\nThe study has a prospective and a retrospective arm\n\nProspective Arm Design: This is a prospective, randomized, partially-blinded pilot study. Randomization for the study will be done in 2 stages.\n\nThe first stage of randomization will randomize subjects to either the early or late initiation of sirolimus. At this stage of the randomization, subject will have a 30% chance of being in group 1 (early-initiation of sirolimus), and a 70% chance of being in group 2 (diagnostic-guided sirolimus group).\n\nThe second stage randomization will be done only on subjects in group 2 (diagnostic-guided sirolimus group) at the time of their first annual heart transplant review. At the time of their annual heart transplant review, subjects in group 2 will have a 50% chance of being in group 2A (CAV diagnosed by angiogram), and a 50% chance of being in group 2B (CAV diagnosed by intravascular ultrasound).\n\nGroup 1: Initiate sirolimus at 6 months after transplant\n\nGroup 2A: Initiate sirolimus after development of angiographic stenosis of \\>70% in a major epicardial vessel or \\>50% in the left main artery\n\nGroup 2B: Initiate sirolimus after development of maximal intimal thickness of 0.5 mm on intravascular ultrasound\n\nRetrospective Arm\n\nThe main objective of this retrospective study is to compare a treatment strategy based on the diagnosis of CAV by intravascular ultrasound to a strategy guided by angiogram.\n\nDesign: This is a randomized, partially-blinded pilot study. Subjects will be randomized 1:1 to one of two groups. At the time of the randomization, the subject will have a 50% chance of being in group 1 (initiation of sirolimus when CAV is diagnosed by angiogram) and a 50% chance of being in group 2. (Initiation of sirolimus when CAV is diagnosed by IVUS)\n\nPrimary Endpoints for Prospective and Retrospective Arms\n\n1. Change in maximal intimal thickness at 1, 2, 3 and 4 years\n2. Combination of significant coronary artery disease (as described above), death, major rejection episodes, and decrease in global ejection function of more than 10% from baseline at 3 and 4years.\n\nSecondary endpoints for Prospective and Retrospective Arms\n\n1. Mean MIT at 1, 2, 3, and 4 years\n2. Percent atheroma volume at 1,2,3 and 4 years\n3. Death from CAV, death from any cause, myocardial infarction, need for PCI, number of hospitalizations, infection rates, evidence of restrictive physiology, arrhythmic event related to CAV or pulmonary hypertension at 4 years.\n4. Change in small artery elasticity at 1, 2, 3, and 4 years\n5. Change in endothelial progenitor cell count at 1 and 2 years\n6. Change in biomarkers (see table) at 1 and 2 years'}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['ADULT', 'OLDER_ADULT'], 'minimumAge': '18 Years', 'healthyVolunteers': False, 'eligibilityCriteria': 'Inclusion Criteria\n\nFor Prospective Arm:\n\n* 18 years or older\n* Successful orthotropic heart transplant within 6 months of enrollment\n\nInclusion Criteria\n\nFor Retrospective Arm:\n\n* 18 years or older\n* Successful orthotropic heart transplant within 6 months to 3 years of enrolment\n* Less than moderate CAV by angiogram or IVUS\n\nExclusion Criteria\n\nFor Prospective Arm:\n\n* Greater than minimal baseline coronary disease\n* Chronic kidney disease with creatinine \\>2mg/dl\n* Baseline (1 month) ejection fraction \\< 50%\n* IV contrast allergy\n* Rejection within 3 months of enrollment\n* Sensitivity to sirolimus or its derivatives\n* Prior sirolimus use\n\nExclusion Criteria\n\nFor Retrospective Arm:\n\n* Significant baseline (one month) coronary artery disease (\\>50% in one or more vessels by angiogram or MIT \\>0.5 by IVUS)\n* Chronic kidney disease with creatinine \\>2mg/dl\n* Baseline (1 month) ejection fraction \\< 50%\n* IV contrast allergy\n* Rejection within 3 months prior to enrollment\n* Sensitivity to sirolimus or its derivatives\n* Prior sirolimus use'}, 'identificationModule': {'nctId': 'NCT01305395', 'acronym': 'STOPCAV', 'briefTitle': 'Strategies To Prevent Cardiac Allograft Vasculopathy Related Events in Heart Transplant Recipients', 'organization': {'class': 'OTHER', 'fullName': 'University of Minnesota'}, 'officialTitle': 'Early Vs Late Sirolimus-Initiation Strategies To Prevent Cardiac Allograft Vasculopathy Related Events in Heart Transplant Recipients', 'orgStudyIdInfo': {'id': '1007M85473'}}, 'armsInterventionsModule': {'armGroups': [{'type': 'EXPERIMENTAL', 'label': 'Early Intervention Arm', 'description': 'Initiate sirolimus within 6 months of heart transplant', 'interventionNames': ['Drug: Sirolimus']}, {'type': 'EXPERIMENTAL', 'label': 'Late Intervention Arm: Group 2A', 'description': 'Initiate sirolimus after CAV is diagnosed by angiogram', 'interventionNames': ['Drug: Sirolimus']}, {'type': 'EXPERIMENTAL', 'label': 'Retrospective Arm: Angiogram group', 'description': 'Start sirolimus after CAV diagnosed is by angiogram', 'interventionNames': ['Drug: Sirolimus']}, {'type': 'EXPERIMENTAL', 'label': 'Late Intervention Arm: Group 2B', 'description': 'Start sirolimus after CAV is diagnosed by IVUS', 'interventionNames': ['Drug: Sirolimus']}, {'type': 'EXPERIMENTAL', 'label': 'Retrospective Arm: Intravascular Ultrasound', 'description': 'Sirolimus after CAV is diagnosed by IVUS', 'interventionNames': ['Drug: Sirolimus']}], 'interventions': [{'name': 'Sirolimus', 'type': 'DRUG', 'otherNames': ['Rapamycin'], 'description': 'Will initiate sirolimus within 6 months of heart transplant', 'armGroupLabels': ['Early Intervention Arm']}, {'name': 'Sirolimus', 'type': 'DRUG', 'otherNames': ['Rapamycin'], 'description': 'Will start sirolimus after CAV has been diagnosed by angiogram', 'armGroupLabels': ['Late Intervention Arm: Group 2A']}, {'name': 'Sirolimus', 'type': 'DRUG', 'otherNames': ['Rapamycin'], 'description': 'Will start sirolimus after CAV has been diagnosed by intravascular ultrasound', 'armGroupLabels': ['Late Intervention Arm: Group 2B']}, {'name': 'Sirolimus', 'type': 'DRUG', 'otherNames': ['Rapamycin'], 'description': 'Will start sirolimus after they develop CAV by angiogram', 'armGroupLabels': ['Retrospective Arm: Angiogram group']}, {'name': 'Sirolimus', 'type': 'DRUG', 'otherNames': ['Rapamycin'], 'description': 'Will start sirolimus after CAV has been diagnosed by intravascular ultrasound', 'armGroupLabels': ['Retrospective Arm: Intravascular Ultrasound']}]}, 'contactsLocationsModule': {'locations': [{'zip': '55455', 'city': 'Minneapolis', 'state': 'Minnesota', 'country': 'United States', 'facility': 'Cardiology Division, University of Minnesota', 'geoPoint': {'lat': 44.97997, 'lon': -93.26384}}], 'overallOfficials': [{'name': 'Monica M Colvin-Adams, MD, MS', 'role': 'PRINCIPAL_INVESTIGATOR', 'affiliation': 'University of Minnesota'}]}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'University of Minnesota', 'class': 'OTHER'}, 'responsibleParty': {'type': 'SPONSOR'}}}}