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

January 23, 2017 updated by: University of Minnesota

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

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

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

Study Type

Interventional

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Minnesota
      • Minneapolis, Minnesota, United States, 55455
        • Cardiology Division, University of Minnesota

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Early Intervention Arm
Initiate sirolimus within 6 months of heart transplant
Drug: Sirolimus
Will initiate sirolimus within 6 months of heart transplant
Other Names:
  • Rapamycin
Drug: Sirolimus
Will start sirolimus after CAV has been diagnosed by angiogram
Other Names:
  • Rapamycin
Drug: Sirolimus
Will start sirolimus after CAV has been diagnosed by intravascular ultrasound
Other Names:
  • Rapamycin
Drug: Sirolimus
Will start sirolimus after they develop CAV by angiogram
Other Names:
  • Rapamycin
Experimental: Late Intervention Arm: Group 2A
Initiate sirolimus after CAV is diagnosed by angiogram
Drug: Sirolimus
Will initiate sirolimus within 6 months of heart transplant
Other Names:
  • Rapamycin
Drug: Sirolimus
Will start sirolimus after CAV has been diagnosed by angiogram
Other Names:
  • Rapamycin
Drug: Sirolimus
Will start sirolimus after CAV has been diagnosed by intravascular ultrasound
Other Names:
  • Rapamycin
Drug: Sirolimus
Will start sirolimus after they develop CAV by angiogram
Other Names:
  • Rapamycin
Experimental: Retrospective Arm: Angiogram group
Start sirolimus after CAV diagnosed is by angiogram
Drug: Sirolimus
Will initiate sirolimus within 6 months of heart transplant
Other Names:
  • Rapamycin
Drug: Sirolimus
Will start sirolimus after CAV has been diagnosed by angiogram
Other Names:
  • Rapamycin
Drug: Sirolimus
Will start sirolimus after CAV has been diagnosed by intravascular ultrasound
Other Names:
  • Rapamycin
Drug: Sirolimus
Will start sirolimus after they develop CAV by angiogram
Other Names:
  • Rapamycin
Experimental: Late Intervention Arm: Group 2B
Start sirolimus after CAV is diagnosed by IVUS
Drug: Sirolimus
Will initiate sirolimus within 6 months of heart transplant
Other Names:
  • Rapamycin
Drug: Sirolimus
Will start sirolimus after CAV has been diagnosed by angiogram
Other Names:
  • Rapamycin
Drug: Sirolimus
Will start sirolimus after CAV has been diagnosed by intravascular ultrasound
Other Names:
  • Rapamycin
Drug: Sirolimus
Will start sirolimus after they develop CAV by angiogram
Other Names:
  • Rapamycin
Experimental: Retrospective Arm: Intravascular Ultrasound
Sirolimus after CAV is diagnosed by IVUS
Drug: Sirolimus
Will initiate sirolimus within 6 months of heart transplant
Other Names:
  • Rapamycin
Drug: Sirolimus
Will start sirolimus after CAV has been diagnosed by angiogram
Other Names:
  • Rapamycin
Drug: Sirolimus
Will start sirolimus after CAV has been diagnosed by intravascular ultrasound
Other Names:
  • Rapamycin
Drug: Sirolimus
Will start sirolimus after they develop CAV by angiogram
Other Names:
  • Rapamycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
1. Change in maximal intimal thickness
Time Frame: 1, 2, 3 and 4 years
1, 2, 3 and 4 years

Secondary Outcome Measures

Outcome Measure
Time Frame
Mean maximal intima thickness
Time Frame: 1, 2, 3, and 4 years
1, 2, 3, and 4 years
Percent atheroma volume
Time Frame: 1,2,3 and 4 years
1,2,3 and 4 years
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.
at 4 years.
Change in small artery elasticity
Time Frame: At 1, 2, 3, and 4 years
At 1, 2, 3, and 4 years
Change in endothelial progenitor cell count
Time Frame: At 1 and 2 years
At 1 and 2 years
Change in biomarkers
Time Frame: At 1 and 2 years
At 1 and 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Minnesota

Investigators

  • Principal Investigator: Monica M Colvin-Adams, MD, MS, University of Minnesota

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2010

Primary Completion (Actual)

January 1, 2015

Study Completion (Actual)

January 1, 2015

Study Registration Dates

First Submitted

February 25, 2011

First Submitted That Met QC Criteria

February 25, 2011

First Posted (Estimate)

February 28, 2011

Study Record Updates

Last Update Posted (Estimate)

January 24, 2017

Last Update Submitted That Met QC Criteria

January 23, 2017

Last Verified

January 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1007M85473

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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