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

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.

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.

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.