Eculizumab Therapy for Chronic Complement-Mediated Injury in Kidney Transplantation

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Alexion Pharmaceuticals
Information provided by (Responsible Party):
Sanjay Kulkarni, Yale University
ClinicalTrials.gov Identifier:
NCT01327573
First received: March 30, 2011
Last updated: March 27, 2014
Last verified: March 2014
  Purpose

This study is designed to assess the effectiveness of eculizumab in recipients of kidney transplantation with donor-specific antibodies (DSA) and worsening kidney function and to assess if eculizumab improves endothelial cell injury in the kidney.

The investigators hypothesize that complement inhibition with eculizumab will reduce allograft injury, resulting from less complement-mediated injury of endothelial cells and less endothelial cell activation.


Condition Intervention Phase
Kidney; Complications, Allograft
Drug: eculizumab
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Eculizumab Therapy for Chronic Complement-Mediated Injury in Kidney Transplantation: A Randomized, Open-Label, Pilot Intervention Trial

Resource links provided by NLM:


Further study details as provided by Yale University:

Primary Outcome Measures:
  • Percent change in GFR [ Time Frame: baseline, 6 months ] [ Designated as safety issue: No ]
    Percent change is calculated as the 6-month GFR minus the baseline GFR, divided by the baseline GFR Percent change will be compared between treatment groups with stratification by C4d status


Secondary Outcome Measures:
  • Number of circulating endothelial cells with evidence of injury and bound antibody and/or complement [ Time Frame: baseline, 3,6,9 months ] [ Designated as safety issue: No ]
    mixed effects model to compare trajectory of in number of circulation endothelial cells with evidence of injury and bound antibody and/or complement between treatment groups

  • Number of endothelial expressed genes that correlate with humoral rejection [ Time Frame: baseline, 3,6,9 months ] [ Designated as safety issue: No ]
    mixed effects models to compare trajectory of number of endothelial expressed genes that correlate with humoral rejection between treatment groups

  • Change in GFR [ Time Frame: Baseline, 3,6,9,12 months ] [ Designated as safety issue: No ]
    Compare trajectories of GFR change and percent GFR change between treatment groups using repeated GFR measurements

  • Safety Analysis [ Time Frame: baseline, 3,6,9,12 month ] [ Designated as safety issue: Yes ]
    Tabulation of treatment-emergent adverse events (categorical) by treatment group as well as evaluation of changes in laboratory parameters (CBC, chemistries) (continuous)


Enrollment: 16
Study Start Date: March 2011
Estimated Study Completion Date: February 2015
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Eculizumab

eculizumab will be given in addition to standard immunosuppression regimen (oral tacrolimus, MMF [mycophenolate mofetil

], prednisone)

Drug: eculizumab
  • Eculizumab Induction 600mg IV every 7 days for 4 doses
  • Eculizumab 900mg IV 7 days later
  • Eculizumab Maintenance 900mg IV every 14 days for total of 26 weeks
Other Names:
  • h5G1.1-mAb
  • Soliris
No Intervention: no additional therapy
patients in this arm will receive standard immunosuppression regimen (oral tacrolimus, MMF, prednisone only, no additional therapy

Detailed Description:

This study will address the clinical challenge that currently exists in the management of kidney transplant recipients who have developed de novo DSA, have deteriorating graft function, yet have no established treatment alternative.

This is a randomized, open-label, pilot intervention trial. Post transplant patients with deteriorating renal function (defined as 20% reduction in GFR) will be screened for the development of DSA and biopsied for the presence of C4d deposition. All patients with DSA and those meeting inclusion/exclusion criteria will undergo protocol renal biopsy and will be assessed for C4d deposition. Participants will be randomized to treatment with eculizumab plus standard of care (SOC) or SOC only. Randomization will be stratified by C4d status (C4d+/C4d-) with 10 subjects (7 eculizumab, 3 SOC only) in each stratum.

Eculizumab is an antibody that has been developed to inhibit the complement protein C5. Eculizumab will be delivered via IV according to the following schedule:

  • Eculizumab Induction 600mg IV every 7 days for 4 doses
  • Eculizumab 900mg IV 7 days later
  • Eculizumab Maintenance 900mg IV every 14 days for total of 26 weeks
  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Kidney transplant recipients greater than 6 months from the date of transplant
  • Must be on standard immunosuppression: tacrolimus, mycophenolate mofetil, prednisone and have stable tacrolimus trough levels over past 3 months
  • Deteriorating renal function, as defined by 20% reduction in GFR (MDRD calculation)
  • Presence of DSA, as defined as MFI > 1100
  • Renal biopsy demonstrating no diffuse, irreversible end-stage organ injury (i.e. stage IV Fibrosis)
  • Renal biopsy demonstrating C4d deposition (stratum 1) or no C4d deposition (stratum 2)

Exclusion Criteria:

  • History of CMV, BK, HSV or other viral infections
  • History of chronic, recurrent bacterial infections
  • Evidence of tubulitis on renal biopsy or other morphological features of acute cellular rejection or acute humoral rejection
  • Renal biopsy demonstrating diffuse, irreversible end-stage organ injury
  • Absolute GFR < 25 (MDRD calculation)
  • Inability to provide informed consent
  • History of poor vascular access
  • Refusal to use double barrier contraception during study participation
  • Patients actively enrolled in other clinical trials
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01327573

Locations
United States, Connecticut
Yale University
New Haven, Connecticut, United States, 06520
Sponsors and Collaborators
Sanjay Kulkarni
Alexion Pharmaceuticals
Investigators
Principal Investigator: Sanjay Kulkarni, MD Yale University
  More Information

Publications:
Responsible Party: Sanjay Kulkarni, Associate Professor, Yale University
ClinicalTrials.gov Identifier: NCT01327573     History of Changes
Other Study ID Numbers: AI-EC-0017
Study First Received: March 30, 2011
Last Updated: March 27, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Yale University:
chronic kidney allograft injury
complement protein
eculizumab
Kidney transplantation

Additional relevant MeSH terms:
Complement System Proteins
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 19, 2014