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

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ClinicalTrials.gov Identifier: NCT02013037
Recruitment Status : Enrolling by invitation
First Posted : December 17, 2013
Last Update Posted : August 22, 2017
Sponsor:
Collaborator:
Alexion Pharmaceuticals
Information provided by (Responsible Party):
Jignesh Patel, MD, PhD, Cedars-Sinai Medical Center

Brief Summary:
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), prevents antibody-mediated rejection in patients with high antibody production and prolongs long-term cardiac transplant survival.

Condition or disease Intervention/treatment Phase
Antibody-mediated Rejection Hyperacute Rejection of Cardiac Transplant Left Ventricular Dysfunction Cardiac Allograft Vasculopathy Heart Graft Dysfunction Drug: Eculizumab Phase 4

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 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). The trial will enroll a total of 10 "sensitized" patients with a panel reactive antibody score greater than 70%, who are not previously or currently enrolled in another ongoing trial. The use of Eculizumab will be un-blinded to all study and research practitioner participants. A historical cohort of 10 additional patients will also be utilized for comparison.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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]
Study Start Date : November 2012
Estimated Primary Completion Date : October 2017
Estimated Study Completion Date : March 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Eculizumab

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 Name: Soliris

No Intervention: Historical Cohort
A historical cohort of heart transplant recipients at Cedars-Sinai Medical Center with a panel reactive antibody (PRA) ≥ 70%, who have not received Eculizumab intervention.



Primary Outcome Measures :
  1. Incidence 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.


Secondary Outcome Measures :
  1. Incidence of 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

  2. Incidence of 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

  3. Incidence of Acute Cellular Rejection (ACR) and/or Antibody Mediated Rejection (AMR) [ Time Frame: up to 1 year post heart transplant ]

    The following events will be assessed during the first year post transplant:

    1. The incidence of acute cellular rejection (ACR) ≥ 2R.
    2. The incidence of antibody-mediated rejection (AMR) ≥ 2.

  4. Patient Survival at 12 months Post Heart Transplantation [ Time Frame: 1 year post heart transplant ]
  5. Development of Cardiac Allograft Vasculopathy (CAV) at 1 year post transplant [ Time Frame: 1 year post heart transplant ]
    The development of CAV will be determined by intravascular ultrasound, as defined by a change in site-matched maximal intimal thickness from baseline to one year.

  6. Presence of Inflammatory and Complement Biomarkers at routine endomyocardial biopsies [ Time Frame: up to 1 year post heart transplant ]
    The presence of inflammatory and complement cascade biomarkers, (such as C3, C4, C5a and C5-b9) will be assessed at routine endomyocardial biopsies during the first year post heart transplant.

  7. Change in Panel Reactive Antibody (PRA) from baseline to 1 year post transplant [ Time Frame: up to 1 year post heart transplant ]
  8. Presence of Donor Specific Antibody (DSA) [ Time Frame: up to 1 year post heart transplant ]
    The presence and strength of donor-specific antibodies will be assessed during the first year post heart transplant.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02013037


Locations
United States, California
Cedars Sinai Medical Center, Heart Institute
Los Angeles, California, United States, 90048
Sponsors and Collaborators
Cedars-Sinai Medical Center
Alexion Pharmaceuticals
Investigators
Principal Investigator: Jignesh Patel, M.D., Ph.D. Cedars Sinai Medical Center and Heart Institute

Publications:

Responsible Party: Jignesh Patel, MD, PhD, Medical Director of Heart Transplant Program, Cedars Sinai Heart Institute, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier: NCT02013037     History of Changes
Other Study ID Numbers: CSR 205237
Pro00028970 ( Other Identifier: Cedars-Sinai Medical Ctr. IRB )
First Posted: December 17, 2013    Key Record Dates
Last Update Posted: August 22, 2017
Last Verified: August 2017

Keywords provided by Jignesh Patel, MD, PhD, Cedars-Sinai Medical Center:
cardiac transplantation
immunosuppression
acute cellular rejection
antibody mediated rejection
sensitization
antibody production in cardiac patients
panel reactive antibodies
desensitization strategies in heart transplant patients
complement activation
complement c3d and c4d deposition
terminal complement inhibition
complement C5 binding
Eculizumab
monoclonal antibody
donor specific antibodies

Additional relevant MeSH terms:
Ventricular Dysfunction
Vascular Diseases
Ventricular Dysfunction, Left
Heart Diseases
Cardiovascular Diseases
Antibodies
Immunoglobulins
Immunologic Factors
Physiological Effects of Drugs