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Bortezomib in Late Antibody-mediated Kidney Transplant Rejection (BORTEJECT)

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ClinicalTrials.gov Identifier: NCT01873157
Recruitment Status : Completed
First Posted : June 7, 2013
Last Update Posted : March 23, 2017
Sponsor:
Collaborator:
Medical University Innsbruck
Information provided by (Responsible Party):
Farsad Eskandary, Medical University of Vienna

Brief Summary:
Late antibody-mediated rejection (AMR) after kidney transplantation is defined as a separate rejection entity. So far, no appropriate treatment has been established for this rejection type. One promising strategy could be the targeting of alloantibody-producing plasma cells. There is now accumulating evidence that the proteasome inhibitor Bortezomib may substantially affect the function and integrity of non-malignant alloantibody-secreting plasma cells. The impact of this compound on the course of late AMR , however, has not yet been systematically investigated. In the planned phase IIa study we will examine the effect of Bortezomib on late AMR after kidney transplantation. We plan an initial cross-sectional HLA antibody screening of 1000 kidney transplant recipients to identify patients with detectable donor-specific antibodies (DSA). DSA-positive recipients will be subjected to kidney allograft biopsy to detect morphological features consistent with AMR. Forty-four patients with late AMR will be included in a randomized double-blind placebo-controlled parallel-group intervention trial. Patients in the active group will receive two cycles of Bortezomib (4 x 1.3 mg/m2). The primary end point will be the course of estimated GFR over 24 months after randomization. Secondary endpoints are the course of DSA levels and protein excretion, measured GFR after 24 months, transplant and patient survival, and the development of acute and chronic morphological lesions in 24-month protocol biopsies. Our study will clarify the impact of an innovative anti-humoral strategy on the deleterious effects of late AMR processes.

Condition or disease Intervention/treatment Phase
Late Rejection of Renal Transplant Antibody-mediated Rejection Drug: Bortezomib Drug: Placebo Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 44 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Bortezomib in Late Antibody-mediated Kidney Transplant Rejection (BORTEJECT Study)
Study Start Date : December 2013
Actual Primary Completion Date : February 2015
Actual Study Completion Date : February 28, 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Bortezomib

Arm Intervention/treatment
Placebo Comparator: Placebo (NaCl solution)

Patients will receive two cycles of Placebo (NaCl solution) at an interval of three months.

Each cycle will consist of intravenously administered (within 3-5 seconds) Placebo twice weekly on days 1, 4, 8 and 11.

Drug: Placebo

Patients will receive two cycles of Placebo (NaCl solution) at an interval of three months.

Each cycle will consist of intravenously administered (within 3-5 seconds) Placebo twice weekly on days 1, 4, 8 and 11.

Other Name: NaCl solution

Active Comparator: Bortezomib (Velcade®)

Patients will receive two cycles of Bortezomib (Velcade®) at an interval of three months.

Each cycle will consist of intravenously administered (within 3-5 seconds) Bortezomib 1.3 mg/m2 twice weekly on days 1, 4, 8 and 11.

Drug: Bortezomib

Patients will receive two cycles of Bortezomib (Velcade®) at an interval of three months.

Each cycle will consist of intravenously administered (within 3-5 seconds) Bortezomib 1.3 mg/m2 twice weekly on days 1, 4, 8 and 11.

Other Name: Velcade®




Primary Outcome Measures :
  1. Change of eGFR slopes over time [ Time Frame: Change from baseline eGFR at 24 months ]

    Peripheric venous blood samples (4ml) will be obtained after 0, 6, 12, 18 an 24 months to assess the change of eGFR slopes over time.

    In case of loss of follow-up the GFR is assumed to be 0ml/min.



Secondary Outcome Measures :
  1. Change of HLA antibody (DSA) levels over time [ Time Frame: Change from baseline HLA antibody (DSA) level at 24 months ]

    Peripheric venous blood samples (10mL) will be obtained after 0, 6, 12, 18 and 24 months to assess DSA levels by Luminex® technology.

    • Maximum and sum of MFI of DSA
    • Number of DSA
    • Broadness of sensitization (virtual PRA)

  2. All-cause mortality [ Time Frame: At 24 months after randomization ]
    Survival will be assessed after 12 and 24 months after randomization

  3. Graft loss [ Time Frame: At 24 months after randomization ]
    Graft loss will be assessed after 12 and 24 months after randomization with or without re-transplantation

  4. Exact measured GFR by Chromium-51 EDTA (Cr-EDTA) clearance method [ Time Frame: Change from baseline GFR at 24 months after randomization ]
    Cr-EDTA GFR will be assessed by measuring the clearance of a defined peripheric administered dose of Chromium-51 EDTA according to a standard protocol.

  5. Change in urine proteine excretion over time [ Time Frame: Change from baseline urine proteine excretion at 24 months after randomization ]
    Protein excretion (protein/creatinine ratio) will be measured in 24h urine at 0, 6, 12, 18 and 24 months after randomization.


Other Outcome Measures:
  1. Occurrence of biopsy-proven acute rejection necessitating rejection treatment [ Time Frame: At month 24 after randomization ]
    Diagnosed at protocol biopsy after month 24 after randomization or whenever clinically indicated

  2. Acute AMR score in a protocol biopsy [ Time Frame: At month 24 after randomization ]

    Acute AMR score (0-9)

    Sum of:

    • Glomerulitis 0, 1, 2, 3
    • Peritubular capillaritis 0, 1, 2, 3
    • C4d in peritubular capillaries 0, 1, 2, 3

  3. Chronic AMR score in a protocol biopsy [ Time Frame: At month 24 after randomization ]

    Chronic AMR score (0-9)

    Sum of:

    • Transplant glomerulopathy 0, 1, 2, 3
    • Peritubular capillary basement membrane lamellation 0, 1, 2, 3
    • Chronic vasculopathy 0, 1, 2, 3



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Part A (Screening for DSA, cross-sectional)

  • Written informed consent
  • Age > 18 years
  • Functioning allograft after ≥180 days
  • eGFR >20 ml/min/1.73 m2

Exclusion Criteria:

Part A (Screening for DSA, cross-sectional)

  • Patients actively participating in another clinical trial
  • Female subject is pregnant or lactating
  • Acute rejection treatment <1 month before screening
  • Acute deterioration of graft function due to suspected acute rejection
  • Active viral, bacterial or fungal infection precluding bortezomib treatment
  • Active malignant disease precluding intensified immunosuppressive therapy
  • Serious medical or psychiatric illness likely to interfere with participation in the study
  • Documented intolerance of Bortezomib, boron or mannitol

Inclusion Criteria:

Part B (Interventional study)

  • Written informed consent
  • Age > 18 years
  • Functioning allograft after ≥180 days
  • eGFR >20 ml/min/1.73 m2
  • HLA class I and/or II DSA-positive
  • A kidney biopsy result showing Glomerulitis and/or peritubular capillaritis and/or transplant glomerulopathy and/or peritubular capillary (PTC) basement membrane lamellation (with or without C4d in PTC).

Exclusion Criteria:

Part B (Interventional study)

  • Patients actively participating in another clinical trial
  • Female subject is pregnant or lactating
  • Acute rejection treatment <1 month before screening
  • Acute deterioration of graft function due to suspected acute rejection
  • Active viral, bacterial or fungal infection precluding Bortezomib treatment
  • Active malignant disease precluding intensified immunosuppressive therapy
  • Serious medical or psychiatric illness likely to interfere with participation in the study
  • Documented intolerance of Bortezomib, boron or mannitol
  • Thrombocytopenia <30 G/l within 2 weeks before enrolment
  • Neutrophil count <1 G/l within 2 weeks before enrolment
  • Peripheral neuropathy ≥grade 2
  • T-cell-mediated rejection classified Banff grade >I
  • De novo or recurrent severe thrombotic microangiopathy
  • Polyoma virus nephropathy
  • De novo or recurrent glomerulonephritis in the allograft

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): NCT01873157


Locations
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Austria
Medical University of Vienna, Department of Nephrology and Dialysis
Vienna, Austria, 1090
Sponsors and Collaborators
Medical University of Vienna
Medical University Innsbruck
Investigators
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Principal Investigator: Georg Böhmig, MD Medical University of Vienna, Department of Nephrology and Dialysis

Additional Information:
Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Farsad Eskandary, Farsad Eskandary, MD, Medical University of Vienna
ClinicalTrials.gov Identifier: NCT01873157     History of Changes
Other Study ID Numbers: KLI 190
2012-002857-41 ( EudraCT Number )
First Posted: June 7, 2013    Key Record Dates
Last Update Posted: March 23, 2017
Last Verified: March 2017

Keywords provided by Farsad Eskandary, Medical University of Vienna:
Kidney transplantation
Antibody formation
Graft rejection
Proteasome inhibitors
Randomized controlled trial

Additional relevant MeSH terms:
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Bortezomib
Pharmaceutical Solutions
Antibodies
Immunoglobulins
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents