Dosing Regimen of Eculizumab Added to Conventional Treatment in Positive Cross Match Living 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 Antibody-mediated Rejection (AMR) in Positive Crossmatch Living Donor Kidney Transplantation

A strongly positive crossmatch has long been considered an absolute contraindication to kidney transplantation and most patients with anti-human leukocyte antigen (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. Our group has performed more than 200 such transplants providing the possibility of transplant to previously untransplantable patients. Despite our best efforts, transplantation in these patients is still complicated by a high rate of acute humoral rejection (AHR).

Patients included in this study will be those who have demonstrable anti-HLA antibody specific for their living donor. It is our hypothesis that blockade of terminal complement activation at the time of transplant in combination with our current protocols will reduce the incidence of AHR in patients with anti-donor HLA antibody.

Study Overview

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

Detailed Description

The eculizumab dosing regimen was modified from that used in the treatment of paroxysmal nocturnal hemoglobinuria and consisted of 1200 mg immediately prior to transplantation, 600 mg on postoperative day 1, and 600 mg weekly thereafter for 4 weeks. At week 4, assessment of DSA levels was performed. Eculizumab was discontinued in patients whose DSA had significantly decreased (B flow crossmatch channel shift<200). In patients with persistently high DSA and thus believed to have continued high risk for AMR, eculizumab treatment continued (1200 mg week 5, and then every 2 weeks). Another DSA assessment was performed at week 9 and eculizumab was discontinued if the B flow crossmatch channel shift was <200.

The eculizumab group were compared to a historical control group consisting of consecutive transplants between 1/1/2005 and 1/10/2017 who met the inclusion criteria. The historical control group had been treated with a similar plasma exchange based protocol without eculizumab.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • 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:

1. 18 years of age

2. Has end stage renal disease (ESRD) and is to receive a kidney transplant from a living donor (LD) to whom he/she has either:

   1. A positive crossmatch requiring pretransplant desensitization (defined as a positive T-cell FCXM of greater than or equal to 300 but less than 450 prior to desensitization, or as a positive B-cell FCXM of > 300 but < 450 prior to desensitization with demonstrable Class II donor specific alloantibody (DSA) on solid-phase assays). Subsequent to desensitization, patient must have, at the time of transplant, a T-cell and B-cell FCXM less than 300; or
   2. A positive crossmatch not requiring desensitization (defined as FCXM between 200 and 299)
3. Willing to comply with the protocol
4. 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
5. Willing and able to give written informed consent
6. Vaccinated against Neisseria meningitides (quadrivalent vaccine), Pneumococcus or H. influenzae at least two weeks prior to beginning desensitization

Exclusion Criteria:

1. Unstable cardiovascular condition
2. Previous splenectomy
3. Active bacterial or other infection which is clinically significant in the opinion of the investigator
4. Known or suspected hereditary complement deficiency
5. Participation in any other investigational drug study or was exposed to an investigational drug or device within 30 days of randomization
6. Pregnant, breast-feeding, or intending to conceive during the course of the study, including the two month follow-up period after drug discontinuation
7. Known hypersensitivity to the treatment drug or any of its excipients
8. History of illicit drug use or alcohol abuse within the previous year
9. History of meningococcal disease
10. 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)
11. Previously been enrolled in this trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Eculizumab; Patients received eculizumab intravenously according to details provided in the intervention description.

Drug: 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 B cell flow cytometry cross match (FCXM). Patients with B cell FCXM less than 200 will stop eculizumab treatment. Patients with B cell FCXM greater than or equal to 200 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.; In addition, eculizumab 600 mg will be administered immediately after each plasmapheresis (PP) and immediately after any fresh frozen plasma (FFP) that is given post-transplant during the treatment period; Other Names: Soliris

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Antibody-Mediated Rejection (AMR) in the First 3 Months After Living Donor Kidney Transplantation	AMR can cause acute graft loss or shorten allograft survival. Renal allograft biopsies were obtained percutaneously using ultrasound guidance processed for light microscopy and immunofluorescence for peritubular capillary staining for C4d. All biopsies were reviewed by a pathologist in a blinded fashion. AMR was diagnosed using standard Banff criteria in combination with graft dysfunction (increase in serum creatinine >/=0.3 mg/dL over nadir.)	up to 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients Developing High DSA Levels at Less Than or Equal to 3 Months	High DSA levels were defined as B flow cross match channel shift >350 at any time point in the first 3 months.	3 months
Number of Patients Requiring Splenectomy	A splenectomy is a surgical operation involving removal of the spleen. Splenectomy was performed for severe AMR in the setting of a rising serum creatinine (usually >2.0) and a rising serum DSA level despite daily plasma exchange treatments.	1 year
Graft Dysfunction in First Month Post Transplant	(Maximum serum creatinine-nadir serum creatinine)	1 month
Length of Follow-up	Following the completion of dosing, subjects were to return for follow-up visits at 3 and 6 months post transplant to obtain biopsies and collect follow-up data. Subjects who continued the drug for 12 months were to receive their final assessment at 15 months.	up to 15 months
Number of Subjects With Graft Survival at One Year	Graft survival means the kidney has not been rejected by the body.	1 year
Number of Subjects Receiving Posttransplant Plasma Exchange (PE)	Plasma exchange is needed when there is poor kidney functioning, and donor specific alloantibody (DSA) is high	up to one year
Transplant Glomerulopathy Incidence at One Year	Transplant glomerulopathy is a morphologic lesion of renal allografts that is characterized histologically by duplication and/or multilayering of the glomerular basement membrane. It is widely accepted as a manifestation of chronic antibody-mediated rejection (AMR). This is determined by histology.	1 year

Collaborators and Investigators

• Sponsor: Mark Stegall
• Collaborators: Alexion Pharmaceuticals

Publications and helpful links

General Publications

• Stegall MD, Diwan T, Raghavaiah S, Cornell LD, Burns J, Dean PG, Cosio FG, Gandhi MJ, Kremers W, Gloor JM. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant. 2011 Nov;11(11):2405-13. doi: 10.1111/j.1600-6143.2011.03757.x. Epub 2011 Sep 22. Erratum In: Am J Transplant. 2013 Jan;13(1):241.
• Bentall A, Tyan DB, Sequeira F, Everly MJ, Gandhi MJ, Cornell LD, Li H, Henderson NA, Raghavaiah S, Winters JL, Dean PG, Stegall MD. Antibody-mediated rejection despite inhibition of terminal complement. Transpl Int. 2014 Dec;27(12):1235-43. doi: 10.1111/tri.12396. Epub 2014 Aug 20.

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 1, 2008
• Primary Completion (ACTUAL): May 1, 2017
• Study Completion (ACTUAL): August 1, 2017

Study Registration Dates

• First Submitted: April 28, 2008
• First Submitted That Met QC Criteria: April 30, 2008
• First Posted (ESTIMATE): May 2, 2008

Study Record Updates

• Last Update Posted (ACTUAL): June 26, 2018
• Last Update Submitted That Met QC Criteria: May 23, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Transplant; Kidney; donor
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Eculizumab
• Other Study ID Numbers: 07-007208

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No