Safety & Tolerability of Berinert® (C1 Inhibitor) Therapy to Prevent Rejection

This study has been completed.
Sponsor:
Collaborator:
CSL Behring
Information provided by (Responsible Party):
Stanley Jordan, MD, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier:
NCT01134510
First received: May 26, 2010
Last updated: July 9, 2014
Last verified: July 2014

May 26, 2010
July 9, 2014
August 2011
November 2013   (final data collection date for primary outcome measure)
Post-transplant biopsy to identify rejection episodes [ Time Frame: 6 month ] [ Designated as safety issue: No ]
Subjects will have a routine kidney biopsy 6 month after transplant to screen for episodes of acute rejection
Post-transplant biopsy to identify rejection episodes [ Time Frame: 1 month ] [ Designated as safety issue: No ]
Subjects will have a routine kidney biopsy 1 month after transplant to screen for episodes of acute rejection
Complete list of historical versions of study NCT01134510 on ClinicalTrials.gov Archive Site
Serum creatinine (and other markers) will be checked at every study visit to Serum creatinine for monitoring of allograft function up to 12 months post-transplant. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
Serum creatinine (and other markers) will be checked at every study visit to monitor allograft function up to 12 months post-transplant.
Serum creatine (and other markers) will be checked at every study visit to Serum creatine for monitoring of allograft function up to 12 months post-transplant. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
Serum creatine (and other markers) will be checked at every study visit to monitor allograft function up to 12 months post-transplant.
Not Provided
Not Provided
 
Safety & Tolerability of Berinert® (C1 Inhibitor) Therapy to Prevent Rejection
A Phase I/II Trial to Evaluate the Safety & Tolerability of Berinert® (C1 Inhibitor) Therapy to Prevent Complement-Dependent, Antibody-Mediated Rejection Post-Transplant in Highly-HLA Sensitized Patients"

Organ transplantation offers the only hope for a normal life for patients with end-stage renal disease on dialysis (ESRD). For the highly-sensitized patient, patients with antibodies to human leukocyte antigens (HLA), transplantation is extremely difficult or impossible since pre-formed antibodies will cause severe rejection and loss of transplanted organs. Approximately 30% of the transplant list in the U.S. is considered sensitized (have detectable antibodies to HLA antigens). These anti-HLA (anti-Human Leukocyte Antigen antibodies) pose a significant barrier to transplantation that has recently been successfully addressed using desensitization therapies with IVIG, rituximab and/or plasmapheresis (PE). Despite the success of these therapies, post-transplant AMR and chronic AMR (CAMR) remain significant problems. Recent data suggests that addition of Berinert (C1 Inhibitor) to post-transplant treatment regimen may significantly reduce incidence of AMR.

Twenty highly-sensitized patients who have undergone desensitization treatment and are awaiting kidney transplant will be enrolled in the study. Once transplanted these patients will be started on the standard of care post-transplant immunosuppressive protocol. In addition patients will receive Berinert 20 units/ kg daily x 3 days, then twice weekly x 3 weeks. At the end of Berinert treatment a kidney biopsy will be performed. Subjects will be followed for 6 months to assess safety and efficacy of the study protocol.

Single center, Phase I/II, randomized The trial will examine the safety and efficacy of human C1 INH given post-transplant to reduce or prevent complement-dependent, antibody-mediated rejection (AMR) in 20 subjects (adult) who are highly-HLA sensitized (HS),(Panel Reactive Antibodies >30% (PRA), have undergone desensitization with IVIG + rituximab and/or plasmapheresis and are awaiting LD/DD kidney transplant. Once transplant offers are entertained, a donor-specific crossmatch will be performed to detect anti-HLA antibodies and donor-specific anti-HLA antibodies (DSA) which are associated with acute rejection or graft loss. (These anti-HLA antibodies may result naturally or from previous pregnancy, transfusions, or prior transplants.) If acceptable crossmatches and DSA levels are seen after desensitization, the patients will proceed to LD/DD transplantation. Patients receiving transplants will have pre-transplant labs obtained for C1 INH levels, C3 and C4 at transplant. In addition to the standard post-transplant immunosuppressive protocol, participating patients will receive placebo or 20U/kg C1 INH twice weekly X 4 weeks. At the end of the treatment, a protocol biopsy will be performed to assess the allograft for evidence of AMR, including C4d staining. Since ~25% of HS patients experience AMR post-transplant and 85% of these AMR episodes occur in the 1st post-transplant month, we feel the assessment of the potential impact of C1 INH therapy is best assessed in this time period. After completion of the C1 INH therapy, patients will be followed for an additional 6M to assess allograft function and AMR episodes as well as DSA.

The subjects will be followed to determine the proportion who develop evidence of AMR within 6M of completion of the study. In addition we will asses the transplanted patients to determine the number who sustain a viable and functioning kidney allograft for 6 months. All subjects will be evaluated on an intent-to-treat basis. The subject accrual rate will be limited to no more than five subjects per month in the initial three months to assure safety to all subjects. Repeat laboratories will be performed at the completion of C1 INH therapy to determine effect on levels and correlation with any potential events.

Interventional
Phase 1
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Kidney Transplantation
Biological: C1 Esterase Inhibitor
C1 Esterase Inhibitor 20 units/kg vs Placebo twice weekly x 4 weeks
Other Name: Berinert
  • Experimental: C1 esterase inhibitor
    10 subjects will receive C1 esterase inhibitor in addition to standard of care immunosuppressive therapy.
    Intervention: Biological: C1 Esterase Inhibitor
  • Placebo Comparator: Normal saline
    10 subjects placebo in addition to standard of care immunosuppressive therapy.
    Intervention: Biological: C1 Esterase Inhibitor

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
20
November 2013
November 2013   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • End-stage renal disease.
  • No known contraindications for therapy with IGIV10%/Rituximab or C1 INH.
  • Age 18-65 years at the time of screening.
  • PRA > 50% demonstrated on 3 consecutive samples, Patient highly-HLA sensitized and a candidate for LD/DD transplantation after desensitization at CSMC.
  • At transplant, patient must have DSA/CMX+ non-HLA identical donor. Subject/Parent/Guardian must be able to understand and provide informed consent.

Exclusion Criteria:

  • Lactating or pregnant females.
  • Women of child-bearing age who are not willing or able to practice FDA-approved forms of contraception.
  • HIV-positive subjects.
  • Subjects who test positive for HBV infection [positive HBVsAg, HBVcAg, or HBVeAg/DNA] or HCV infection [positive Anti-HCV (EIA) and confirmatory HCV RIBA].
  • Subjects with active TB.
  • Subjects with selective IgA deficiency, those who have known anti-IgA antibodies, and those with a history of anaphylaxis or severe systemic responses to any part of the clinical trial material.
  • Subjects who have received or for whom multiple organ transplants are planned.
  • Recent recipients of any licensed or investigational live attenuated vaccine(s) within two months of the screening visit (including but not limited to any of the following:
  • Adenovirus [Adenovirus vaccine live oral type 7] Varicella [Varivax] Hepatitis A [VAQTA] Rotavirus [Rotashield] Yellow fever [Y-F-Vax] Measles and mumps [Measles and mumps virus vaccine live] Measles, mumps, and rubella vaccine [M-M-R-II] Sabin oral polio vaccine Rabies vaccines [IMOVAX Rabies I.D., RabAvert])
  • A significantly abnormal general serum screening lab result defined as a WBC < .0 X 103/ml, a Hgb < 8.0 g/dL, a platelet count < 100 X 103/ml, , an SGOT > 5X upper limit of normal, and an SGPT >5X upper limit of normal range.
  • Individuals deemed unable to comply with the protocol.
  • Subjects with active CMV or EBV infection as defined by CMV-specific serology (IgG or IgM) and confirmed by quantitative PCR with or without a compatible illness.
  • Subjects with a known history of previous myocardial infarction within one year of screening.
  • Subjects with a history of clinically significant thrombotic episodes, and subjects with active peripheral vascular disease.
  • Use of investigational agents within 4 weeks of participation.
  • Know allergy/sensitivity to C1INH infusions
Both
18 Years to 65 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01134510
C1INH001CSMC
No
Stanley Jordan, MD, Cedars-Sinai Medical Center
Stanley Jordan, MD
CSL Behring
Principal Investigator: Stanley C Jordan, MD Cedars-Sinai Medical Center
Cedars-Sinai Medical Center
July 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP