Eculizumab Therapy for Subclinical Antibody-mediated Rejection in Kidney Transplantation

NCT02113891 | Withdrawn Phase 1 DMC

• 1 other identifier: P101004
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

Advances in renal transplantation have increased life-expectancy in patients with end-stage kidney disease. Conventional immunosuppressive drugs prevent efficiently early allograft losses due to T-cell mediated rejection. However, emerging data suggest that the majority of late kidney failures may be attributable to antibody-mediated rejection (AMR), which poorly responds to the currently available therapeutics. Complement-fixing donor-specific anti-HLA antibodies are associated with the worst outcome in keeping with the well-established role of the complement in AMR pathogenesis. Eculizumab, the first licenced complement blocker, has been found efficient in reducing the occurrence of AMR lesions in highly sensitized patients. A few reports also suggest that complement blockade may be of great value as salvage therapy for graft-threatening severe AMR. However, no information is available in the literature about the interest of complement blockade in curbing the progression of subclinical acute AMR to chronic AMR. The purpose of this study is to determine whether complement blockade with eculizumab is effective and safe in the treatment of subclinical AMR in sensitized kidney transplant recipients. Despite appropriate therapies, up to 75% of patients having received a renal transplant with preformed donor-specific antibody display subclinical AMR on their 3-month protocol biopsy. Subclinical AMR is defined by histological lesions of AMR concomitant with stable graft function. Moreover, the extent of these lesions at 3 month post-transplant correlates with the occurrence of irreversible scars and chonic antibody-mediated rejection on the 12-month biopsy. This study aims to explore the efficacy and safety of eculizumab in patients exhibiting subclinical AMR on their 3 month-post-transplant biopsy, to reduce or even normalize microcirculation inflammation, and to prevent chronic rejection (transplant glomerulopathy) on the 12 month-screening biopsy. Eculizumab-treated patients will be compared with historical controls, matched for the lesions on the 3 month biopsy.

Conditions

Subclinical Acute Antibody-mediated Rejection in Kidney Transplantation

Keywords

Antibody-mediated rejection; Complement blockade; Eculizumab; Kidney transplantation

Outcome Measures

Primary Outcomes (4)

• Microcirculation inflammation

  Compare trajectories of g (0-3) and ptc (0-3) Banff scores

  12-month screening biopsies

• Transplant glomerulopathy

  Compare trajectories of cg (0-3) Banff score

  12 month screening biopsies

• Microcirculation inflammation

  Compare trajectories of g (0-3) and ptc (0-3) Banff scores

  3 month screening biopsies

• Transplant glomerulopathy

  Compare trajectories of cg (0-3) Banff score

  3 month screening biopsies

Secondary Outcomes (11)

• Measured Glomerular Filtration Rate (Iohexol clearance)

  12 months post-transplant

• Incidence of adverse effects

  at 15 months post-transplant

• Incidence of biopsy-proven acute rejection

  at 12 months post-transplant

• CH50

  at 15 months post-transplant (baseline, each infusion, study completion)

• Endothelial Microparticles and Progenitors

  Baseline, 1, 3, 6 and 9 months

Study Arms (1)

Eculizumab

EXPERIMENTAL

Eculizumab will be given in addition to standard immunosuppression regimen (tacrolimus, mycophenalte mofeti, prednisone)

Drug: Eculizumab

Interventions

Eculizumab DRUG

Eculizumab induction: 900 mg IV every 7 days for 4 doses, a fifth 1200 mg dose 7 days later Eculizumab maintenance: 15 1200 mg doses every 14 days. (each patient will receive a total of 20 eculizumab doses during the whole treatment period from 3 month to 12 month post-transplant).

Also known as: Soliris

Eculizumab

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female patients aged 18 -75 years.
• Patients having received a kidney transplant from a living or deceased donor
• Patients with stable renal function
• Sensitized patient with at least one anti-HLA class II DSA (MFI \> 1000) within the first 3 months.
• Adequate 3-month-protocol biopsy exhibiting microcirculation inflammation defined by glomerulitis Banff score (g) superior or egal 2 and /or peri-tubular capillaritis Banff score (ptc) superior or egal 2, AND the sum of scores g + ptc superior or egal 3.
• C4d positive staining on 3-month-protocol biopsy
• Adequate 3-month-protocol biopsy exhibiting limited scarred areas as defined as IF/TA score (ci + ct) inferior or egal 2 and no or minimal transplant glomerulopathy (cg inferior or egal 1)
• Patients who have given written informed consent to participate in all aspects of the study.
• Females of childbearing potential must have a negative pregnancy test within 48 hours prior to the first eculizumab administration.

You may not qualify if:

• Patients with known hypersensitivity to eculizumab or drugs with similar chemical structure.
• Patients having experienced and having been treated for an acute antibody-mediated rejection within the first 3 months post-transplant
• Patients with multi-organ transplant
• Female patients who are pregnant, lactating or of child bearing potential and not practicing an approved method of birth control.
• Patients with a known malignancy or history of malignancy other than excised basal or squamous cell carcinoma of the skin
• HBV, HCV or HIV-chronically infected patients
• Patients with evidence of severe liver disease, including abnormal liver profile (aspartate aminotransferase \[AST\], alanine aminotransferases \[ALT\] or total bilirubin \> 3 times upper limit of normal at screening.
• Patients with current severe infection.
• Ongoing meningococcal infection
• Patient with systemic lupus erythematosus disease and / or anti-phospholipid antibodies
• Patients with any surgical or medical condition, which in the opinion of the investigator precludes enrollment in this trial
• Patients who live far from the transplant center and are unable to comply with all study visits.
• Long-term anticoagulation therapy or other contraindication to graft biopsies
• Positive BKV viremia during the first three months post-transplant

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Institut National de la Santé Et de la Recherche Médicale, France: collaborator
• Alexion Pharmaceuticals, Inc.: collaborator
• URC-CIC Paris Descartes Necker Cochin: collaborator

Related Publications (4)

• Loupy A, Suberbielle-Boissel C, Hill GS, Lefaucheur C, Anglicheau D, Zuber J, Martinez F, Thervet E, Mejean A, Charron D, Duong van Huyen JP, Bruneval P, Legendre C, Nochy D. Outcome of subclinical antibody-mediated rejection in kidney transplant recipients with preformed donor-specific antibodies. Am J Transplant. 2009 Nov;9(11):2561-70. doi: 10.1111/j.1600-6143.2009.02813.x. Epub 2009 Sep 22.

  PMID: 19775320 BACKGROUND

• 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 BACKGROUND

• Loupy A, Lefaucheur C, Vernerey D, Prugger C, Duong van Huyen JP, Mooney N, Suberbielle C, Fremeaux-Bacchi V, Mejean A, Desgrandchamps F, Anglicheau D, Nochy D, Charron D, Empana JP, Delahousse M, Legendre C, Glotz D, Hill GS, Zeevi A, Jouven X. Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med. 2013 Sep 26;369(13):1215-26. doi: 10.1056/NEJMoa1302506.

  PMID: 24066742 BACKGROUND

• Zuber J, Le Quintrec M, Krid S, Bertoye C, Gueutin V, Lahoche A, Heyne N, Ardissino G, Chatelet V, Noel LH, Hourmant M, Niaudet P, Fremeaux-Bacchi V, Rondeau E, Legendre C, Loirat C; French Study Group for Atypical HUS. Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation. Am J Transplant. 2012 Dec;12(12):3337-54. doi: 10.1111/j.1600-6143.2012.04252.x. Epub 2012 Sep 7.

  PMID: 22958221 BACKGROUND

MeSH Terms

Interventions

eculizumab

Study Officials

• Christophe LEGENDRE, MD

  Service de Transplantation Rénale, Hôpital Necker Université Paris Descartes 149 rue de Sèvres 75015 Paris, France

  STUDY DIRECTOR

Study Design

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

Study Record Dates

• First Submitted: November 21, 2013
• First Posted: April 15, 2014
• Study Start: February 1, 2015
• Primary Completion: July 1, 2017
• Study Completion: November 1, 2017
• Last Updated: November 20, 2025

Record last verified: 2025-10