Dosing Regimen of Eculizumab Added to Conventional Treatment in Positive Crossmatch Deceased Donor Kidney Transplant

Phase 1

Terminated

Conditions: Kidney Transplant

Interventions: Drug: Eculizumab

Registration Number: NCT01106027

Lead Sponsor: Mayo Clinic

Brief Summary: The purpose of this study is to test whether a dosing regimen of eculizumab in addition to standard posttransplant care in positive crossmatch deceased donor kidney transplant recipients will reduce the incidence of acute humoral rejection (AHR).

Patients included in this study will be those who have demonstrable anti-human leukocyte antigen (HLA) antibody specific for their deceased donor. It is our hypothesis that blockade of terminal complement activation with eculizumab at the time of transplant in combination with our current protocols will reduce the incidence of AHR in recipients of deceased donor kidney transplants who have anti-donor HLA antibody

Detailed Description: A strongly positive crossmatch has long been considered an absolute contraindication to kidney transplantation and most patients with anti-HLA antibody never were able to receive a kidney transplant. Over the past decade, significant progress has been made in overcoming early antibody-mediated renal allograft injury. Despite our best efforts, transplantation in these patients is still complicated by a high rate of acute humoral rejection.

While we have successfully transplanted more than 250 patients with DSA using living donors, applying these protocols to recipients of deceased donors has been problematic. This primarily is due to the fact that in contrast to living donation, the timing of a deceased donor kidney transplant cannot be planned. This leads to inadequate time to perform the multiple pretransplant plasmapheresis treatments needed to achieve a safe level of DSA at transplant. Thus, there is a major unmet need to develop therapy that will allow for the successful transplantation of deceased donor kidneys in recipients who have DSA.

* At the time of deceased donor kidney transplantation, patients will undergo one plasmapheresis prior to surgery.

* Patients will be given 1200 mg of eculizumab intravenously over 30 minutes, 1 hour prior to surgery.

* Patients will be given 900 mg of eculizumab on Day 1 post-transplant.

* Patients will then be given 900 mg of eculizumab weekly through 4 weeks post-transplant

* At week 4, patients will be assessed for DSA. Patients with total DSA normalized values \<5000 will stop eculizumab treatment. Patients with total DSA normalized values \>5000 will continue eculizumab treatment every 14 days from week 5 through week 9. The dose will be increased to 1200 mg and dosing will now be every 2 weeks instead of weekly. Similar "discontinuation assessments" will be performed at week 9, 26, 39 and 52.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 2

Inclusion Criteria

18 years of age
Has end stage renal disease (ESRD) and is to receive a kidney transplant from a deceased donor (DD) to whom he/she has a positive T or B cell crossmatch >200 at the time of transplant and DSA demonstrated by solid phase assays.
Willing to comply with the protocol
Females of child-bearing potential must have a negative pregnancy test (serum β-HCG) and sexually active females must agree to use a reliable and medically approved method of contraception
Willing and able to give written informed consent
Vaccinated against Neisseria meningitides (quadrivalent vaccine), Pneumococcus and H. influenzae at least two weeks prior to beginning desensitization

Exclusion Criteria

Unstable cardiovascular condition
Previous splenectomy
Active bacterial or other infection which is clinically significant in the opinion of the investigator
Known or suspected hereditary complement deficiency
Participation in any other investigational drug study or was exposed to an investigational drug or device within 30 days of randomization
Pregnant, breast-feeding, or intending to conceive during the course of the study, including a one month follow-up period after drug discontinuation
Known hypersensitivity to the treatment drug or any of its excipients
History of illicit drug use or alcohol abuse within the previous year
History of meningococcal disease
Medical condition that, in the opinion of the investigator, might interfere with the patient's participation in the study, pose an added risk for the patient, or confound the assessment of the patient (e.g. severe cardiovascular or pulmonary disease)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Eculizumab	Eculizumab	Patients will be given 1200 mg of eculizumab intravenously over 30 minutes, 1 hour prior to surgery. Patients will be given 900 mg of eculizumab on Day 1 post-transplant. Patients will then be given 900 mg of eculizumab weekly through 4 weeks post-transplant. At week 4, patients will be assessed for donor specific anti-donor human leukocyte antigen (HLA) antibody (DSA). Patients with total DSA normalized values \<5000 will stop eculizumab treatment. Patients with total DSA normalized values \>5000 will continue eculizumab treatment every 14 days from week 5 through week 9. The dose will be increased to 1200 mg and dosing will now be every 2 weeks instead of weekly.

Primary Outcome Measures

Name	Time	Method
Number of Subjects With Acute Humoral Rejection (AHR) up to One Year Post Transplant.	1 year posttransplant	Diagnosis of AHR will be based histological findings using Banff '05 criteria.

Secondary Outcome Measures