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Eculizumab Therapy for Chronic Complement-Mediated Injury in Kidney Transplantation

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ClinicalTrials.gov Identifier: NCT01327573
Recruitment Status : Unknown
Verified March 2014 by Sanjay Kulkarni, Yale University.
Recruitment status was:  Active, not recruiting
First Posted : April 1, 2011
Last Update Posted : March 28, 2014
Sponsor:
Collaborator:
Alexion Pharmaceuticals
Information provided by (Responsible Party):
Sanjay Kulkarni, Yale University

Brief Summary:

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 or disease Intervention/treatment Phase
Kidney; Complications, Allograft Drug: eculizumab Phase 1

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

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Eculizumab Therapy for Chronic Complement-Mediated Injury in Kidney Transplantation: A Randomized, Open-Label, Pilot Intervention Trial
Study Start Date : March 2011
Estimated Primary Completion Date : September 2014
Estimated Study Completion Date : February 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Eculizumab

Arm Intervention/treatment
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



Primary Outcome Measures :
  1. Percent change in GFR [ Time Frame: baseline, 6 months ]
    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 :
  1. Number of circulating endothelial cells with evidence of injury and bound antibody and/or complement [ Time Frame: baseline, 3,6,9 months ]
    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

  2. Number of endothelial expressed genes that correlate with humoral rejection [ Time Frame: baseline, 3,6,9 months ]
    mixed effects models to compare trajectory of number of endothelial expressed genes that correlate with humoral rejection between treatment groups

  3. Change in GFR [ Time Frame: Baseline, 3,6,9,12 months ]
    Compare trajectories of GFR change and percent GFR change between treatment groups using repeated GFR measurements

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



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): 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

Publications:
Responsible Party: Sanjay Kulkarni, Associate Professor, Yale University
ClinicalTrials.gov Identifier: NCT01327573     History of Changes
Other Study ID Numbers: AI-EC-0017
First Posted: April 1, 2011    Key Record Dates
Last Update Posted: March 28, 2014
Last Verified: March 2014

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

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