Strategies To Prevent Cardiac Allograft Vasculopathy Related Events in Heart Transplant Recipients (STOPCAV)

This study has suspended participant recruitment.
(Due in part, to reduced transplant volume and enrollment has been difficult.)
Sponsor:
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT01305395
First received: February 25, 2011
Last updated: March 13, 2013
Last verified: March 2013

February 25, 2011
March 13, 2013
November 2010
January 2015   (final data collection date for primary outcome measure)
1. Change in maximal intimal thickness [ Time Frame: 1, 2, 3 and 4 years ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT01305395 on ClinicalTrials.gov Archive Site
  • Mean maximal intima thickness [ Time Frame: 1, 2, 3, and 4 years ] [ Designated as safety issue: No ]
  • Percent atheroma volume [ Time Frame: 1,2,3 and 4 years ] [ Designated as safety issue: No ]
  • 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 [ Time Frame: at 4 years. ] [ Designated as safety issue: No ]
  • Change in small artery elasticity [ Time Frame: At 1, 2, 3, and 4 years ] [ Designated as safety issue: No ]
  • Change in endothelial progenitor cell count [ Time Frame: At 1 and 2 years ] [ Designated as safety issue: No ]
  • Change in biomarkers [ Time Frame: At 1 and 2 years ] [ Designated as safety issue: No ]
  • Mean maximal intima thickness [ Time Frame: 1, 2, 3, and 4 years ] [ Designated as safety issue: No ]
  • Percent atheroma volume [ Time Frame: 1,2,3 and 4 years ] [ Designated as safety issue: No ]
  • 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 [ Time Frame: at 4 years. ] [ Designated as safety issue: No ]
  • Change in small artery elasticity [ Time Frame: At 1, 2, 3, and 4 years ] [ Designated as safety issue: No ]
  • Change in endothelial progenitor cell count [ Time Frame: At 1 and 2 years ] [ Designated as safety issue: No ]
  • Change in biomarkers [ Time Frame: At 1 and 2 years ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Strategies To Prevent Cardiac Allograft Vasculopathy Related Events in Heart Transplant Recipients
Early Vs Late Sirolimus-Initiation Strategies To Prevent Cardiac Allograft Vasculopathy Related Events in Heart Transplant Recipients
  1. Early initiation of sirolimus will prevent or delay the development of intimal thickening and subsequent graft failure.
  2. 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.
  3. 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.
  4. Small artery elasticity predicts progression of cardiac allograft vasculopathy and is modified by sirolimus
  5. Patients who have no progression of CAV will have favorable improvement in biomarkers and endothelial cells compared to patients who have progression of CAV

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:

  1. 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.
  2. To determine the effect of IVUS-guided initiation of sirolimus on short-term and long-term outcomes vs. angiogram-guided initiation of sirolimus
  3. To determine whether prevention of progression of CAV diagnosed by IVUS prevents graft dysfunction or death related to CAV or heart failure.
  4. 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.

The study has a prospective and a retrospective arm

Prospective Arm Design: This is a prospective, randomized, partially-blinded pilot study. Randomization for the study will be done in 2 stages.

The 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).

The 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).

Group 1: Initiate sirolimus at 6 months after transplant

Group 2A: Initiate sirolimus after development of angiographic stenosis of >70% in a major epicardial vessel or >50% in the left main artery

Group 2B: Initiate sirolimus after development of maximal intimal thickness of 0.5 mm on intravascular ultrasound

Retrospective Arm

The 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.

Design: 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)

Primary Endpoints for Prospective and Retrospective Arms

  1. Change in maximal intimal thickness at 1, 2, 3 and 4 years
  2. 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.

Secondary endpoints for Prospective and Retrospective Arms

  1. Mean MIT at 1, 2, 3, and 4 years
  2. Percent atheroma volume at 1,2,3 and 4 years
  3. 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.
  4. Change in small artery elasticity at 1, 2, 3, and 4 years
  5. Change in endothelial progenitor cell count at 1 and 2 years
  6. Change in biomarkers (see table) at 1 and 2 years
Interventional
Not Provided
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Cardiac Allograft Vasculopathy
  • Drug: Sirolimus
    Will initiate sirolimus within 6 months of heart transplant
    Other Name: Rapamycin
  • Drug: Sirolimus
    Will start sirolimus after CAV has been diagnosed by angiogram
    Other Name: Rapamycin
  • Drug: Sirolimus
    Will start sirolimus after CAV has been diagnosed by intravascular ultrasound
    Other Name: Rapamycin
  • Drug: Sirolimus
    Will start sirolimus after they develop CAV by angiogram
    Other Name: Rapamycin
  • Experimental: Early Intervention Arm
    Initiate sirolimus within 6 months of heart transplant
    Intervention: Drug: Sirolimus
  • Experimental: Late Intervention Arm: Group 2A
    Initiate sirolimus after CAV is diagnosed by angiogram
    Intervention: Drug: Sirolimus
  • Experimental: Retrospective Arm: Angiogram group
    Start sirolimus after CAV diagnosed is by angiogram
    Intervention: Drug: Sirolimus
  • Experimental: Late Intervention Arm: Group 2B
    Start sirolimus after CAV is diagnosed by IVUS
    Intervention: Drug: Sirolimus
  • Experimental: Retrospective Arm: Intravascular Ultrasound
    Sirolimus after CAV is diagnosed by IVUS
    Intervention: Drug: Sirolimus

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Suspended
120
January 2016
January 2015   (final data collection date for primary outcome measure)

Inclusion Criteria

For Prospective Arm:

  • 18 years or older
  • Successful orthotropic heart transplant within 6 months of enrollment

Inclusion Criteria

For Retrospective Arm:

  • 18 years or older
  • Successful orthotropic heart transplant within 6 months to 3 years of enrolment
  • Less than moderate CAV by angiogram or IVUS

Exclusion Criteria

For Prospective Arm:

  • Greater than minimal baseline coronary disease
  • Chronic kidney disease with creatinine >2mg/dl
  • Baseline (1 month) ejection fraction < 50%
  • IV contrast allergy
  • Rejection within 3 months of enrollment
  • Sensitivity to sirolimus or its derivatives
  • Prior sirolimus use

Exclusion Criteria

For Retrospective Arm:

  • Significant baseline (one month) coronary artery disease (>50% in one or more vessels by angiogram or MIT >0.5 by IVUS)
  • Chronic kidney disease with creatinine >2mg/dl
  • Baseline (1 month) ejection fraction < 50%
  • IV contrast allergy
  • Rejection within 3 months prior to enrollment
  • Sensitivity to sirolimus or its derivatives
  • Prior sirolimus use
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01305395
1007M85473
Yes
University of Minnesota - Clinical and Translational Science Institute
University of Minnesota - Clinical and Translational Science Institute
Not Provided
Principal Investigator: Monica M Colvin-Adams, MD, MS University of Minnesota - Clinical and Translational Science Institute
University of Minnesota - Clinical and Translational Science Institute
March 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP