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

A Single Center, Open-label Study to Determine the Safety and Efficacy of a Dosing Regimen of Eculizumab Added to Conventional Treatment in the Prevention of Acute Humoral Rejection (AHR) in Positive Crossmatch Deceased Donor Kidney Transplantation

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

Study Overview

• Status: Terminated
• Conditions: Kidney Transplant
• Intervention / Treatment: Drug: Eculizumab

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.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55901
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

Drug: Eculizumab; Eculizumab 900 mg and 1200 mg, administered intravenously (IV); Other Names: Soliris

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: Alexion Pharmaceuticals
• Investigators: Principal Investigator: Mark Stegall, MD, Mayo Clinic

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2010
• Primary Completion (Actual): August 19, 2016
• Study Completion (Actual): August 19, 2016

Study Registration Dates

• First Submitted: March 29, 2010
• First Submitted That Met QC Criteria: April 15, 2010
• First Posted (Estimate): April 19, 2010

Study Record Updates

• Last Update Posted (Actual): January 31, 2018
• Last Update Submitted That Met QC Criteria: January 8, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Death; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Eculizumab
• Other Study ID Numbers: 09-005627DD

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes