Dosing Regimen of Eculizumab Added to Conventional Treatment in Positive Cross Match Living Donor Kidney Transplant

NCT00670774 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: 07-007208
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Kidney Transplant

Keywords

Kidney; Transplant; donor

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• Number of Patients Developing High DSA Levels at Less Than or Equal to 3 Months

  3 months

• Number of Patients Requiring Splenectomy

  1 year

• Graft Dysfunction in First Month Post Transplant

  1 month

• Length of Follow-up

  up to 15 months

• Number of Subjects With Graft Survival at One Year

  1 year

Study Arms (1)

Eculizumab

EXPERIMENTAL

Patients received eculizumab intravenously according to details provided in the intervention description.

Drug: Eculizumab

Interventions

Eculizumab DRUG

* 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

Also known as: Soliris

Eculizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years of age
• Has end stage renal disease (ESRD) and is to receive a kidney transplant from a living donor (LD) to whom he/she has either:
• 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
• A positive crossmatch not requiring desensitization (defined as FCXM between 200 and 299)
• 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 or H. influenzae at least two weeks prior to beginning desensitization

You may not qualify if:

• 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 the two 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)
• Previously been enrolled in this trial.

Sponsors & Collaborators

• Mark Stegall: lead
• Alexion Pharmaceuticals, Inc.: collaborator

Study Sites (1)

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Related Publications (2)

• 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.

  PMID: 21942930 RESULT

• 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.

  PMID: 24990476 DERIVED

MeSH Terms

Interventions

eculizumab

Results Point of Contact

• Title: Dr. Mark D. Stegall
• Organization: Mayo Clinic

Stegall.Mark@mayo.edu

507-284-6275

Study Officials

• Mark D. Stegall, M.D.

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: April 28, 2008
• First Posted: May 2, 2008
• Study Start: March 1, 2008
• Primary Completion: May 1, 2017
• Study Completion: August 1, 2017
• Last Updated: June 26, 2018
• Results First Posted: June 26, 2018

Record last verified: 2018-05

Locations

US (1)