The De-novo Use of Eculizumab in Presensitized Patients Receiving Cardiac Transplantation (DUET)

April 30, 2021 updated by: Jignesh Patel, MD, PhD, Cedars-Sinai Medical Center

The De-novo Use of Eculizumab Alongside Conventional Therapy in Presensitized Patients Receiving Cardiac Transplantation: An Open-Label, Investigator-Initiated Pilot Trial: [The DUET Cardiac Trial]

All individuals who receive a heart transplant are at risk for developing antibody-mediated rejection (AMR). An antibody is a protein produced by the body's immune system when it detects a foreign substance, called an antigen. The mechanism of an antibody is to attack an antigen. In antibody mediated rejection, antibodies will attack the transplanted heart, causing injury to the heart. The purpose of this investigation is to determine if a study drug, called eculizumab (Soliris), is safe to use in heart transplant recipients, and determine if it reduces risk of antibody-mediated rejection.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The growing proportion of sensitized cardiac recipients presents an additional challenge to the transplant practitioner attempting to minimize the occurrence of antibody mediated rejection (AMR). Patients pre-exposed or "sensitized" to antigen exposing events (i.e.: blood transfusions, multiple pregnancies, prior organ transplantations, ventricular support devices) are more likely to both possess preformed and develop de-novo antibodies. Sensitized patients with panel reactive antibodies > 25% are at risk for increased risk of rejection, development of cardiac allograft vasculopathy and increased mortality after heart transplantation.

A central component of antibody-mediated cell injury is complement activation. The inhibition of terminal complement activation may be the missing link to decreasing possibly both complement-mediated AMR and cellular rejection (CR) by inhibiting both the inflammatory effects of both circulating antibodies and cytokine induced cell death.

Eculizumab is a monoclonal antibody that specifically binds to complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. By this mechanism, eculizumab (Soliris®) inhibits terminal complement mediated intravascular hemolysis in paroxysmal nocturnal hemoglobinuria patients.

This study is a non-randomized, open-label, investigator-initiated safety and efficacy trial investigating the de-novo use of eculizumab alongside conventional therapy to prevent antibody mediated rejection. The duration of the study will include an open enrollment period and at least 12 months of follow-up (post-transplant). We will consent up to 45 eligible patients, highly "sensitized", with a panel reactive antibody score greater than 70%, who are not previously or currently enrolled in another ongoing trial. Of these 45 participants, up to 20 of these patients will be treated with eculizumab (Solaris), the study drug. The use of eculizumab will be un-blinded to all study and research practitioner participants.

Study Type

Interventional

Enrollment (Actual)

36

Phase

  • Phase 3

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
    • California
      • Los Angeles, California, United States, 90048
        • Cedars Sinai Medical Center, Heart Institute

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

16 years to 73 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patient is ≥ 18 years of age.
  • Patient has a panel reactive antibody (PRA) ≥ 70% at any time prior to screening.
  • Patient is considered compliant and intends to be available for a minimum follow-up study period of 1 year.
  • Patient must be vaccinated against Neisseria meningitides at least 2 weeks prior to receiving treatment therapy or receive appropriate antibiotic prophylaxis for the duration of eculizumab treatment if timely vaccination could not be achieved prior to transplantation.
  • Voluntary written informed consent must be obtained before performance of any study-related procedure not considered routine medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
  • Female subject is either post-menopausal or surgically sterilized or willing to use two acceptable methods of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study and for up to 2 months after the last dose of study medication.

Exclusion Criteria:

  • Donor or recipient age is < 18 years or > 75 years.
  • Cold ischemia time is > 6 hours.
  • Current clinical, radiographic, or laboratory evidence of active or latent tuberculosis (TB), as determined by local standard of care.
  • History of active TB within the last 2 years, even if treated.
  • History of active TB greater than 2 years ago, unless there is documentation of adequate treatment according to locally accepted clinical practice.

(Note: Patients at risk of TB reactivation preclude administration of conventional immunosuppression, as determined by the study investigator and based upon appropriate evaluation).

  • Receipt of desensitization treatment with rituximab less than 2 weeks prior to therapy and cluster of differentiation antigen 20 (CD20) count >2%.
  • Receipt of a live vaccine within 4 weeks prior to study entry.
  • Patients with current or recent severe systemic infections within the 2 weeks prior to transplantation.
  • Prior history of splenectomy.

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: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Eculizumab
Administration of Eculizumab to heart transplant recipients at Cedars Sinai Medical Center with a panel reactive antibody (PRA) ≥ 70%, for the prevention of antibody-mediated rejection.
Drug: Eculizumab

At the time of transplantation, 1200mg of Eculizumab will be administered via a 35 minute IV infusion, followed by thymoglobulin 1.5 mg/kg intravenous piggyback (IVPB). The administration of thymoglobulin will be repeated (if blood counts permit) for a total of five doses.

On Day 1 post-transplant, 900 mg of Eculizumab will be given via an IV infusion.

On Day 5 post-transplant, intravenous immunoglobulin (IVIG) 1 gram/kg will be administered daily for two consecutive days.

On post-transplant days 7, 14, and 21 (+/- 2 days) 900mg of Eculizumab will be given via an IV infusion at each scheduled visit.

On post-transplant days 28, 42, and 56 (+/- 2 days) 1200 mg of Eculizumab will be given via an IV infusion at each scheduled visit.

Other Names:
  • Soliris

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants of Pathologic Antibody-Mediated Rejection and Left Ventricular Dysfunction
Time Frame: up to 26 weeks post heart transplant

The efficacy of Eculizumab will be assessed by a composite endpoint of:

  1. the incidence of pathologic AMR with a Grade ≥ 2
  2. the incidence of left ventricular dysfunction, as defined by a left ventricular ejection fraction (LVEF) ≤ 40% or a decrease of >15% from baseline prior to the initiation of Eculizumab treatment.
up to 26 weeks post heart transplant

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Patient Survival at 12 Months Post Heart Transplantation
Time Frame: 1 year post heart transplant
The study will assess overall survival at 12 months following heart transplantation.
1 year post heart transplant
Number of Participants With Hemodynamic Compromise at 6 Months Post Transplant
Time Frame: 6 months post heart transplant

The incidence of patient hemodynamic compromise will be assessed at 6 months post transplant, as defined by any one of the following:

  1. a 20% decrease in LVEF from baseline
  2. a LVEF < 40%
  3. a 25% decrease in cardiac index from baseline
  4. a cardiac index < 2.0
  5. the need for inotropic support
6 months post heart transplant
Number of Participants With Hemodynamic Compromise at 1 Year Post Transplant
Time Frame: 1 year post heart transplant

The incidence of patient hemodynamic compromise will be assessed at one year post transplant, as defined by any one of the following:

  1. a 20% decrease in LVEF from baseline
  2. a LVEF < 40%
  3. a 25% decrease in cardiac index from baseline
  4. a cardiac index < 2.0
  5. the need for inotropic support
1 year post heart transplant
Number of Participants With Antibody Mediated Rejection (AMR)
Time Frame: up to 1 year post heart transplant
The study assessed the number of patients who develop AMR as well as the total number of episodes of AMR.
up to 1 year post heart transplant
Number of Participants With of Acute Cellular Rejection (ACR)
Time Frame: up to 1 year post heart transplant
The study assessed the number of participants with of Acute Cellular Rejection (ACR)
up to 1 year post heart transplant
Development of Cardiac Allograft Vasculopathy (CAV) by Intravascular Ultrasound (IVUS)
Time Frame: up to 1 year post heart transplant
Development of cardiac allograft vasculopathy at 1 year determined by intravascular ultrasound defined as change in site-matched maximal intimal thickness ≥ 0.5mm from baseline to 1 year.
up to 1 year post heart transplant
Number of Participants With Evolution of DSA: Donor Specific Antibody Post Transplantation
Time Frame: Up to 1 year post transplant
Number of Participants who develop de novo donor specific antibody (DSA) in the first year following transplantation was determined.
Up to 1 year post transplant

Collaborators and Investigators

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

Sponsor

Cedars-Sinai Medical Center

Collaborators

Alexion Pharmaceuticals

Investigators

  • Principal Investigator: Jignesh Patel, M.D., Ph.D., Cedars Sinai Medical Center and Heart Institute

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, 2012

Primary Completion (Actual)

December 30, 2019

Study Completion (Actual)

April 30, 2020

Study Registration Dates

First Submitted

December 11, 2013

First Submitted That Met QC Criteria

December 11, 2013

First Posted (Estimate)

December 17, 2013

Study Record Updates

Last Update Posted (Actual)

May 3, 2021

Last Update Submitted That Met QC Criteria

April 30, 2021

Last Verified

April 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CSR 205237
  • Pro00028970 (Other Identifier: Cedars-Sinai Medical Ctr. IRB)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

Individual participant data that supports the results of the study after deidentification and in accordance with Cedars Sinai data sharing agreements.

IPD Sharing Time Frame

Data will be available following publication and ending 3 years following article publication.

IPD Sharing Access Criteria

Data will be available to investigators whose proposed used of the data has been approved by Cedars Sinai IRB.

IPD Sharing Supporting Information Type

  • Study Protocol
  • Statistical Analysis Plan (SAP)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

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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