Bortezomib in Rejection of Kidney Transplants

Condition(s) targeted: Chronic Antibody-mediated Transplant Rejection

Intervention: Bortezomib (Drug); Plasma exchanges and intravenous immunoglobulins (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Assistance Publique - Hôpitaux de Paris

Official(s) and/or principal investigator(s):
Christophe Legendre, MD, PhD, Study Chair, Affiliation: Assistance Publique - Hôpitaux de Paris

Overall contact:
Renaud Snanoudj, MD, PhD, Phone: +33 1 44 49 54 32, Email: renaud.snanoudj@nck.aphp.fr

The purpose of the study is to assess the efficacy of bortezomib, in association with steroids, plasma exchange, and polyclonal intravenous immunoglobulins, in the treatment of chronic antibody mediated rejection due to donor specific anti-HLA antibodies, in kidney transplant recipients

Official title: Treatment of Chronic Active Antibody-mediated Rejection With Bortezomib in Kidney Transplantation

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: histological lesions of humoral rejection and immunodominant donor specific antibody

Secondary outcome:

histological lesions of humoral rejection

immunodominant donor specific antibody

all donor specific antibodies at one year

all donor specific antibodies

Histological lesions

renal function and proteinuria

Safety of bortezomib in renal transplant recipients

Patient and graft survival

T and B lymphocytes subsets with bortezomib

Detailed description: Chronic active antibody-mediated rejection (AMR) is considered as a main cause of late allograft losses in kidney transplant recipients. It is due to the occurrence of de novo donor-specific anti-HLA antibodies (DSA), i. e. antibodies synthetized by the recipient after transplantation against its transplant. There is currently to efficient treatment. The purpose of our study is to determine the efficacy of bortezomib, a proteasome inhibitor, in the treatment of chronic active antibody-mediated rejection, in association with steroids, plasma exchanges, and polyclonal intravenous immunoglobulins. Patients are recipients of a first or a second kidney transplant for more than 6 months. They display de novo DSA i. e. DSA not detected at the last annual systematic screening, and before transplantation. They display signs of chronic active AMR on kidney biopsy i. e. a glomerulitis (g) + peritubular capillaritis (ptc) Banff score g+ptc > 2, with or without severe chronic glomerulopathy (Banff score cg<3). Kidney biopsy may have been performed in three circumstances: 1. detection of de novo DSA on annual screening, 2. proteinuria (> 0. 5 g/24h) or slow graft dysfunction (increase >20% in serum creatinine in a three-month lap) 3. protocol biopsy Primary endpoint is a combined endpoint one year after inclusion, consisting of the stabilization of histological lesions on a new kidney biopsy (delta g+ptc ≤1 and delta cg < 1) and a decrease in DSA mean fluorescence intensity > 50%.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- recipients of a first or a second kidney transplant for more than 6 months

- age over 18 years

- with de novo donor specific antibodies (DSA), i. e. antibodies not detected before

transplantation and at the last annual systematic post-transplant screening

- with histological lesions of chronic active antibody-mediated rejection (glomerulitis

+ peritubular capillaritis banff score > 2 and chronic glomerulopathy cg<3) on a graft biopsy performed because of renal function deterioration, proteinuria, detection of de novo DSA, or on a systematic biopsy

- written informed consent

- Women of child bearing age must have a negative pregnancy test the day of the

inclusion and should use a contraceptive method during the study

- Men old enough to procreate include in the arm Bortezomib have to use during the

Bortezomib treatment and 3 months after

- affiliated with social security health insurance

Exclusion Criteria:

- patient with preformed DSA

- recipient of a 3rd or 4th kidney transplant

- recipient of a transplant combined with another not renal organ

- patient with a history of antibody-mediated rejection during the current

transplantation

- estimated GFR below 30 ml/min/1,73m2

- rapid decline of renal function (increase in serum creatinin > 20% in less than

three months)

- severe transplant glomerulopathy (cg score = 3)

- severe peripheral neuropathy, thrombopenia < 100 000 mm3 , neutropenia < 1000 mm3

and/or an uncontrolled evolutionary infection

- active hepatitis B (positive HBs antigen or HBV DNA), positive hepatitis C serology

or HIV serology

- allergy to bore or bortezomib or to one of the excipient

- hepatic failure, abnormal liver tests (bilirubin >3N, transaminases >3n),

infiltrative pneumopathy, pericarditis

- risk of non-adherence to treatment or protocol

- inclusion in another clinical therapeutic trial

Renaud Snanoudj, MD, PhD, Phone: +33 1 44 49 54 32, Email: renaud.snanoudj@nck.aphp.fr

Hopital Necker Enfants-malades, Paris 75015, France; Recruiting
Renaud Snanoudj, Phone: +33 1 44 49 54 32, Email: renaud.snanoudj@nck.aphp.fr
Laurence lecomte, PhD, Phone: +33171196494, Email: Laurence.lecomte@nck.aphp.fr

Starting date: February 2015
Last updated: April 8, 2015