Antibody-mediated Rejection, Cardiac Allograft Vasculopathy, Heart Graft Dysfunction, Hyperacute Rejection of Cardiac Transplant, Left Ventricular Dysfunction
Conditions
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
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.
Interventions
DRUGEculizumab
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.
Sponsors
Alexion Pharmaceuticals, Inc.
Cedars-Sinai Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants of Pathologic Antibody-Mediated Rejection and Left Ventricular Dysfunction | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Hemodynamic Compromise at 6 Months Post Transplant | 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 |
| Number of Participants With Hemodynamic Compromise at 1 Year Post Transplant | 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 |
| Number of Participants With Antibody Mediated Rejection (AMR) | 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. |
| Patient Survival at 12 Months Post Heart Transplantation | 1 year post heart transplant | The study will assess overall survival at 12 months following heart transplantation. |
| Development of Cardiac Allograft Vasculopathy (CAV) by Intravascular Ultrasound (IVUS) | 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. |
| Number of Participants With Evolution of DSA: Donor Specific Antibody Post Transplantation | 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. |
| Number of Participants With of Acute Cellular Rejection (ACR) | up to 1 year post heart transplant | The study assessed the number of participants with of Acute Cellular Rejection (ACR) |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled following written informed consent for a protocol approved by the Institutional Review Board of Cedars-Sinai Medical Center (NCT02013037).The duration of the study included an open enrollment period and at least 12 months of post-transplant follow-up. All patients worked up for a heart transplant at the Heart Institute at Cedars-Sinai Medical Center (CSMC) with a panel reactive antibody (PRA) ≥ 70% at any time prior to screening.
Pre-assignment details
The trial enrolled a total of 36 sensitized participants age ≥ 18 years with a panel reactive antibody ≥70% at any time prior to study screening. Participants were included in the eculizumab treatment group if at least one donor specific antibody at MFI≥5000 was crossed but with negative prospective complement-dependent cytotoxicity crossmatch. 16 enrolled patients did not receive eculizumab.
Participants by arm
| Arm | Count |
|---|---|
| Eculizumab 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. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Awaiting Transplantation | 7 |
| Overall Study | Death | 6 |
| Overall Study | Transplanted without DSA | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Eculizumab |
|---|---|
| Age, Continuous | 53.3 years |
| Combined transplantation | 2 Participants |
| Long term mechanical circulatory support (MCS) or extra-corporeal membrane oxygena at transplant | 10 Participants |
| Non ischemic heart failure | 15 Participants |
| Pre-transplant diabetes | 7 Participants |
| Pre-transplant hypertension | 8 Participants |
| Prior blood transfusion | 8 Participants |
| Prior pregnancy (women) | 14 Participants |
| Race/Ethnicity, Customized Non-Caucasian | 7 Participants |
| Region of Enrollment United States | 20 participants |
| Retransplantation | 5 Participants |
| Serum creatinine | 1.35 mg/dL |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 4 Participants |
| Time on waiting list | 129 Days |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 8 / 36 |
| other Total, other adverse events | 0 / 36 |
| serious Total, serious adverse events | 13 / 36 |
Outcome results
Primary
Number of Participants of Pathologic Antibody-Mediated Rejection and Left Ventricular Dysfunction
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.
Time frame: up to 26 weeks post heart transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eculizumab | Number of Participants of Pathologic Antibody-Mediated Rejection and Left Ventricular Dysfunction | 4 Participants |
Secondary
Development of Cardiac Allograft Vasculopathy (CAV) by Intravascular Ultrasound (IVUS)
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.
Time frame: up to 1 year post heart transplant
Population: 20 enrolled patients were treated on the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eculizumab | Development of Cardiac Allograft Vasculopathy (CAV) by Intravascular Ultrasound (IVUS) | 1 Participants |
Secondary
Number of Participants With Antibody Mediated Rejection (AMR)
The study assessed the number of patients who develop AMR as well as the total number of episodes of AMR.
Time frame: up to 1 year post heart transplant
Population: 20 participants were treated in the eculizumab study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eculizumab | Number of Participants With Antibody Mediated Rejection (AMR) | 6 Participants |
Secondary
Number of Participants With Evolution of DSA: Donor Specific Antibody Post Transplantation
Number of Participants who develop de novo donor specific antibody (DSA) in the first year following transplantation was determined.
Time frame: Up to 1 year post transplant
Population: 20 enrolled patients were treated on the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eculizumab | Number of Participants With Evolution of DSA: Donor Specific Antibody Post Transplantation | 5 Participants |
Secondary
Number of Participants With Hemodynamic Compromise at 1 Year Post 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
Time frame: 1 year post heart transplant
Population: 20 participants participated in the eculizumab study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eculizumab | Number of Participants With Hemodynamic Compromise at 1 Year Post Transplant | 0 Participants |
Secondary
Number of Participants With Hemodynamic Compromise at 6 Months Post 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
Time frame: 6 months post heart transplant
Population: 20 participants were included in the Eculizumab study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eculizumab | Number of Participants With Hemodynamic Compromise at 6 Months Post Transplant | 0 Participants |
Secondary
Number of Participants With of Acute Cellular Rejection (ACR)
The study assessed the number of participants with of Acute Cellular Rejection (ACR)
Time frame: up to 1 year post heart transplant
Population: 20 participants were treated in the eculizumab study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eculizumab | Number of Participants With of Acute Cellular Rejection (ACR) | 0 Participants |
Secondary
Patient Survival at 12 Months Post Heart Transplantation
The study will assess overall survival at 12 months following heart transplantation.
Time frame: 1 year post heart transplant
Population: 20 participants were included in the Eculizumab study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eculizumab | Patient Survival at 12 Months Post Heart Transplantation | 18 Participants |