Trial Outcomes & Findings for The De-novo Use of Eculizumab in Presensitized Patients Receiving Cardiac Transplantation (NCT NCT02013037)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

36 participants

Primary outcome timeframe

up to 26 weeks post heart transplant

Results posted on

2021-05-03

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	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.
Overall Study STARTED	36
Overall Study COMPLETED	20
Overall Study NOT COMPLETED	16

Reasons for withdrawal

Reasons for withdrawal
Measure	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.
Overall Study Death	6
Overall Study Withdrawal by Subject	1
Overall Study Awaiting Transplantation	7
Overall Study Transplanted without DSA	2

Baseline Characteristics

The analysis population includes only the number of women (16)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Eculizumab n=20 Participants 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.
Sex: Female, Male Female	16 Participants n=20 Participants
Sex: Female, Male Male	4 Participants n=20 Participants
Race/Ethnicity, Customized Non-Caucasian	7 Participants n=20 Participants
Region of Enrollment United States	20 participants n=20 Participants
Non ischemic heart failure	15 Participants n=20 Participants
Time on waiting list	129 Days n=20 Participants
Long term mechanical circulatory support (MCS) or extra-corporeal membrane oxygena at transplant	10 Participants n=20 Participants
Combined transplantation	2 Participants n=20 Participants
Retransplantation	5 Participants n=20 Participants
Prior blood transfusion	8 Participants n=20 Participants
Prior pregnancy (women)	14 Participants n=16 Participants • The analysis population includes only the number of women (16)
Pre-transplant diabetes	7 Participants n=20 Participants
Pre-transplant hypertension	8 Participants n=20 Participants
Serum creatinine	1.35 mg/dL n=20 Participants
Age, Continuous	53.3 years n=20 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Eculizumab n=20 Participants 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. 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.
Number of Participants of Pathologic Antibody-Mediated Rejection and Left Ventricular Dysfunction	4 Participants

SECONDARY outcome

Timeframe: 1 year post heart transplant

Population: 20 participants were included in the Eculizumab study

The study will assess overall survival at 12 months following heart transplantation.

Outcome measures

Outcome measures
Measure	Eculizumab n=20 Participants 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. 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.
Patient Survival at 12 Months Post Heart Transplantation	18 Participants

SECONDARY outcome

Timeframe: 6 months post heart transplant

Population: 20 participants were included in the Eculizumab study

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

Outcome measures

Outcome measures
Measure	Eculizumab n=20 Participants 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. 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.
Number of Participants With Hemodynamic Compromise at 6 Months Post Transplant	0 Participants

SECONDARY outcome

Timeframe: 1 year post heart transplant

Population: 20 participants participated in the eculizumab study

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

Outcome measures

Outcome measures
Measure	Eculizumab n=20 Participants 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. 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.
Number of Participants With Hemodynamic Compromise at 1 Year Post Transplant	0 Participants

SECONDARY outcome

Timeframe: up to 1 year post heart transplant

Population: 20 participants were treated in the eculizumab study

The study assessed the number of patients who develop AMR as well as the total number of episodes of AMR.

Outcome measures

Outcome measures
Measure	Eculizumab n=20 Participants 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. 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.
Number of Participants With Antibody Mediated Rejection (AMR)	6 Participants

SECONDARY outcome

Timeframe: up to 1 year post heart transplant

Population: 20 participants were treated in the eculizumab study

The study assessed the number of participants with of Acute Cellular Rejection (ACR)

Outcome measures

Outcome measures
Measure	Eculizumab n=20 Participants 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. 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.
Number of Participants With of Acute Cellular Rejection (ACR)	0 Participants

SECONDARY outcome

Timeframe: up to 1 year post heart transplant

Population: 20 enrolled patients were treated on the study

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.

Outcome measures

Outcome measures
Measure	Eculizumab n=20 Participants 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. 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.
Development of Cardiac Allograft Vasculopathy (CAV) by Intravascular Ultrasound (IVUS)	1 Participants

SECONDARY outcome

Timeframe: Up to 1 year post transplant

Population: 20 enrolled patients were treated on the study

Number of Participants who develop de novo donor specific antibody (DSA) in the first year following transplantation was determined.

Outcome measures

Outcome measures
Measure	Eculizumab n=20 Participants 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. 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.
Number of Participants With Evolution of DSA: Donor Specific Antibody Post Transplantation	5 Participants

Adverse Events

Eculizumab

Serious events: 13 serious events

Other events: 0 other events

Deaths: 8 deaths

Serious adverse events

Serious adverse events
Measure	Eculizumab n=36 participants at risk 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. 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. 2 deaths were reported in participants who received eculizumab. There were 6 deaths in participants who did not complete the study and did not receive eculizumab.
Infections and infestations Viral infections	16.7% 6/36 • Number of events 6 • 1 year post transplant
Infections and infestations Bacterial Infections	19.4% 7/36 • Number of events 8 • 1 year post transplant
Infections and infestations Fungal infections	5.6% 2/36 • Number of events 2 • 1 year post transplant

Other adverse events

Adverse event data not reported

Additional Information

Dr. Jignesh Patel

Cedars Sinai Smidt Heart Institute

Phone: 310-248-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place