Bortezomib in Rejection of Kidney Transplants (TRIBUTE)

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

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

Study Overview

• Status: Completed
• Conditions: Chronic Antibody-mediated Transplant Rejection
• Intervention / Treatment: Drug: Bortezomib; Drug: Plasma exchanges and intravenous immunoglobulins

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 3 months. They display de novo DSA i.e. DSA not detected the day of transplantation and in pre-transplant sera.. 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 systematically or because of: :

1. detection of de novo DSA ,
2. and /or proteinuria (> 0.5 g/24h)
3. and /or slow graft dysfunction 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%.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France, 75015
    • Hôpital Necker Enfants-Malades

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• recipients of a first or a second kidney transplant for more than 3 months
• age over 18 years
• with de novo donor specific antibodies (DSA), i.e. antibodies not detected the day of transplantation and in pre-transplant sera
• with histological lesions of chronic active antibody-mediated rejection (glomerulitis + peritubular capillaritis banff score and chronic glomerulopathy (g+ptc ≥ 2) on a graft biopsy performed because of renal function deterioration, proteinuria, detection of de novo DSA, or on a systematic biopsy
• written informed consent

• Given the teratogenic risks described in the SPCs of Velcade and Cellcept:

  • Women of child bearing age must have a negative pregnancy test the day of the inclusion and should use at least one effective contraceptive method before start of medication during the treatment and during the study
  • Men old enough to procreate have to use condoms during the treatment and at least 90 days after the last intake of the treatment during the study. Moreover, given SPCs of Cellcept, it is recommended that female partners to use an effective method of contraception treatment and for 90 days after the last mycophenolate intake by the partner male
• affiliated with social security health insurance
• patients with cell rejection lesions associated with chronic humoral rejection lesions active may be included in the study. This rejection can be treated with 3 boluses of 500 mg of methyl prednisolone prior to inclusion.

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 humoral acute rejection during the current transplantation
• estimated GFR below 20 ml/min/1,73m2
• severe transplant glomerulopathy (cg score = 3)
• severe peripheral neuropathy, thrombopenia < 100 000 mm3 , neutropenia < 1000 mm3 and/or an uncontrolled evolutionary infection
• chronic active hepatitis B (positive HBs antigen or HBV DNA), positive chronic hepatitis C and/or known HIV infection
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bortezomib; Five plasma exchanges, two cycles of bortezomib + dexamethasone, 4 courses of polyclonal intravenous immunoglobulins	Drug: Bortezomib; Five plasma exchanges +0.1 g/kg of intravenous immunoglobulins at the end of each course; two cycles of bortezomib (1.3 mg/m2 IV at day-1, day-4, day-8, day-11) + oral dexamethasone (20 mg po at day-1, day-4, day-8, day-11); four courses of polyclonal intravenous immunoglobulins every three weeks (2g/kg, the first two courses are performed simultaneously with the two bortezomib cycles); Other Names: Velcade
Active Comparator: Control; Five plasma exchanges, dexamethasone, 4 courses of polyclonal intravenous immunoglobulins	Drug: Plasma exchanges and intravenous immunoglobulins; Five plasma exchanges +0.1 g/kg of intravenous immunoglobulins at the end of each course; four courses of polyclonal intravenous immunoglobulins every three weeks (2g/kg); oral dexamethasone (20 mg po at day-1, day-3, day-5, day-7 of the two first intravenous immunoglobulins courses)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
histological lesions of humoral rejection and immunodominant donor specific antibody	Between inclusion biopsy and end of study biopsy delta g+ptc ≤1 and delta cg < 1 (Banff score of glomerulitis (g) capillaritis (ptc) and chronic allograft glomerulopathy (cg) Between inclusion and end of study, decrease in mean fluorescence intensity (MFI) of the immunodominant donor specific anti-HLA antibody (DSA with the highest MFI) by Luminex greater than 50%	one year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
histological lesions of humoral rejection	Between inclusion biopsy and end of study biopsy delta g+ptc ≤1 and delta cg < 1 (Banff score of glomerulitis (g) capillaritis (ptc) and chronic allograft glomerulopathy (cg)	one year
immunodominant donor specific antibody	Between inclusion and end of study, decrease in mean fluorescence intensity (MFI) of the immunodominant donor specific anti-HLA antibody (DSA with the highest MFI) by Luminex greater than 50%	one year
all donor specific antibodies at one year	Between inclusion and end of study, variation of the title of each DSA and the sum of the DSAs	one year
all donor specific antibodies	Between inclusion and month-6, evolution in mean fluorescence intensity (MFI) of all donor specific anti-HLA antibodies by Luminex	6 months
Histological lesions	Description of all histological lesions observed at one-year biopsy according to the Banff classification and comparison with inclusion biopsy: acute cellular rejection, interstitial fibrosis and tubular atrophy, chronic vascular lesions (arteriolar hyalinosis, fibro-intimal thickening), chronic rejection (transplant glomerulopathy, fibroproliferative endarteritis)	one year
renal function and proteinuria	Evolution between inclusion and end of study at one-year of serum creatinine, estimated GFR (MDRD formula), proteinuria output, proteinuria/creatinuria ratio	one year
Safety of bortezomib in renal transplant recipients	Infectious and non-infectious adverse events occurring during study in the two arms of treatment	one year
Patient and graft survival		one year
T and B lymphocytes subsets with bortezomib	Flow cytometry study of T and B lymphocytes subsets at inclusion, month-6 and month-12 in patients treated with bortezomib	one year

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Fondation Centaure
• Investigators: Study Chair: Christophe Legendre, MD, PhD, Assistance Publique - Hôpitaux de Paris; Principal Investigator: Renaud Snanoudj, MD, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2015
• Primary Completion (Actual): July 16, 2020
• Study Completion (Actual): July 16, 2020

Study Registration Dates

• First Submitted: July 17, 2014
• First Submitted That Met QC Criteria: July 25, 2014
• First Posted (Estimate): July 28, 2014

Study Record Updates

• Last Update Posted (Actual): September 16, 2020
• Last Update Submitted That Met QC Criteria: September 14, 2020
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: immunosuppressive agents; Chronic antibody-mediated rejection,; transplant rejection, kidney transplantation,; proteasome inhibitor,; anti-HLA antibodies,
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Antibodies; Immunoglobulins; Immunoglobulins, Intravenous; Bortezomib; gamma-Globulins; Rho(D) Immune Globulin
• Other Study ID Numbers: P120119