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

NCT ID: NCT00670774

Last Updated: 2018-06-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 31 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-03-31
• Study Completion Date: 2017-08-31

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.

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.

Conditions

Kidney Transplant

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Eculizumab

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

Group Type: EXPERIMENTAL

Eculizumab

Intervention Type: 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

Interventions

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

Intervention Type: DRUG

Other Intervention Names

Soliris

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Alexion Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: collaborator

Mark Stegall

OTHER

Sponsor Role: lead

Responsible Party

Mark Stegall

MD

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Mark D. Stegall, M.D.

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

Locations

Mayo Clinic

Rochester, Minnesota, United States

Countries

United States

References

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.

Reference Type: RESULT

PMID: 21942930 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 24990476 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

07-007208

Identifier Type: -

Identifier Source: org_study_id