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Bortezomib in Rejection of Kidney Transplants (TRIBUTE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02201576
Recruitment Status : Active, not recruiting
First Posted : July 28, 2014
Last Update Posted : October 21, 2019
Sponsor:
Collaborator:
Fondation Centaure
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:
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

Condition or disease Intervention/treatment Phase
Chronic Antibody-mediated Transplant Rejection Drug: Bortezomib Drug: Plasma exchanges and intravenous immunoglobulins Phase 2

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%.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Treatment of Chronic Active Antibody-mediated Rejection With Bortezomib in Kidney Transplantation
Actual Study Start Date : February 11, 2015
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : July 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Bortezomib
Five plasma exchanges, two cycles of bortezomib + dexamethasone, 4 courses of polyclonal intravenous immunoglobulins
Drug: Bortezomib
  1. Five plasma exchanges +0.1 g/kg of intravenous immunoglobulins at the end of each course
  2. 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)
  3. four courses of polyclonal intravenous immunoglobulins every three weeks (2g/kg, the first two courses are performed simultaneously with the two bortezomib cycles)
Other Name: Velcade

Active Comparator: Control
Five plasma exchanges, dexamethasone, 4 courses of polyclonal intravenous immunoglobulins
Drug: Plasma exchanges and intravenous immunoglobulins
  1. Five plasma exchanges +0.1 g/kg of intravenous immunoglobulins at the end of each course
  2. four courses of polyclonal intravenous immunoglobulins every three weeks (2g/kg)
  3. oral dexamethasone (20 mg po at day-1, day-3, day-5, day-7 of the two first intravenous immunoglobulins courses)




Primary Outcome Measures :
  1. histological lesions of humoral rejection and immunodominant donor specific antibody [ Time Frame: one year ]
    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%


Secondary Outcome Measures :
  1. histological lesions of humoral rejection [ Time Frame: one year ]
    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)

  2. immunodominant donor specific antibody [ Time Frame: one year ]
    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%

  3. all donor specific antibodies at one year [ Time Frame: one year ]
    Between inclusion and end of study, variation of the title of each DSA and the sum of the DSAs

  4. all donor specific antibodies [ Time Frame: 6 months ]
    Between inclusion and month-6, evolution in mean fluorescence intensity (MFI) of all donor specific anti-HLA antibodies by Luminex

  5. Histological lesions [ Time Frame: one year ]
    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)

  6. renal function and proteinuria [ Time Frame: one year ]
    Evolution between inclusion and end of study at one-year of serum creatinine, estimated GFR (MDRD formula), proteinuria output, proteinuria/creatinuria ratio

  7. Safety of bortezomib in renal transplant recipients [ Time Frame: one year ]
    Infectious and non-infectious adverse events occurring during study in the two arms of treatment

  8. Patient and graft survival [ Time Frame: one year ]
  9. T and B lymphocytes subsets with bortezomib [ Time Frame: one year ]
    Flow cytometry study of T and B lymphocytes subsets at inclusion, month-6 and month-12 in patients treated with bortezomib



Information from the National Library of Medicine

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

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

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): NCT02201576


Locations
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France
Hopital Necker Enfants-malades
Paris, France, 75015
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Fondation Centaure
Investigators
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Study Chair: Christophe Legendre, MD, PhD Assistance Publique - Hôpitaux de Paris
Principal Investigator: Renaud Snanoudj, MD, PhD Assistance Publique - Hôpitaux de Paris

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02201576    
Other Study ID Numbers: P120119
First Posted: July 28, 2014    Key Record Dates
Last Update Posted: October 21, 2019
Last Verified: October 2019
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Chronic antibody-mediated rejection,
transplant rejection, kidney transplantation,
proteasome inhibitor,
anti-HLA antibodies,
immunosuppressive agents
Additional relevant MeSH terms:
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Dexamethasone
Dexamethasone acetate
Bortezomib
BB 1101
Antibodies
Immunoglobulins
Immunoglobulins, Intravenous
gamma-Globulins
Rho(D) Immune Globulin
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunologic Factors