Clinical trial NCT02013037: The De-novo Use of Eculizumab in Presensitized Patients Receiving Cardiac Transplantation
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Antibody-mediated Rejection
Hyperacute Rejection of Cardiac Transplant
Left Ventricular Dysfunction
Cardiac Allograft Vasculopathy
Heart Graft Dysfunction
Keywords: 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
Lead sponsor: Cedars-Sinai Medical Center
Sponsor class: OTHER
Collaborators: name: Alexion Pharmaceuticals, Inc.
First posted: 2013-12-17
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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), is safe to use in heart transplant recipients, and determine if it reduces risk of antibody-mediated rejection.

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.

Eligibility 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 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.

Primary outcomes:
measure: Number of Participants of Pathologic Antibody-Mediated Rejection and Left Ventricular Dysfunction
timeFrame: up to 26 weeks post heart transplant
Secondary outcomes:
measure: Patient Survival at 12 Months Post Heart Transplantation
timeFrame: 1 year post heart transplant
measure: Number of Participants With Hemodynamic Compromise at 6 Months Post Transplant
timeFrame: 6 months post heart transplant
measure: Number of Participants With Hemodynamic Compromise at 1 Year Post Transplant
timeFrame: 1 year post heart transplant
measure: Number of Participants With Antibody Mediated Rejection (AMR)
timeFrame: up to 1 year post heart transplant
measure: Number of Participants With of Acute Cellular Rejection (ACR)
timeFrame: up to 1 year post heart transplant
measure: Development of Cardiac Allograft Vasculopathy (CAV) by Intravascular Ultrasound (IVUS)
timeFrame: up to 1 year post heart transplant
measure: Number of Participants With Evolution of DSA: Donor Specific Antibody Post Transplantation
timeFrame: Up to 1 year post transplant
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center, Heart Institute
state: California
Study officials:
affiliation: Cedars Sinai Medical Center and Heart Institute
name: Jignesh Patel, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
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