Bortezomib in Late Antibody-mediated Kidney Transplant Rejection

• Status: Completed
• Trial end date: 2017-02-28
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Medical University of Vienna
• Collaborator: Medical University Innsbruck
• Treatments: Antibodies; Bortezomib; Immunoglobulins; Pharmaceutical Solutions

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