Bortezomib in Late Antibody-mediated Kidney Transplant Rejection

NCT01873157 | Completed Phase 2 DMC

• 2 other identifiers: KLI 1902012-002857-41
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

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.

Conditions

Late Rejection of Renal Transplant; Antibody-mediated Rejection

Keywords

Kidney transplantation; Antibody formation; Graft rejection; Proteasome inhibitors; Randomized controlled trial

Outcome Measures

Primary Outcomes (1)

• Change of eGFR slopes over time

  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.

  Change from baseline eGFR at 24 months

Secondary Outcomes (5)

• Change of HLA antibody (DSA) levels over time

  Change from baseline HLA antibody (DSA) level at 24 months

• All-cause mortality

  At 24 months after randomization

• Graft loss

  At 24 months after randomization

• Exact measured GFR by Chromium-51 EDTA (Cr-EDTA) clearance method

  Change from baseline GFR at 24 months after randomization

• Change in urine proteine excretion over time

  Change from baseline urine proteine excretion at 24 months after randomization

Other Outcomes (3)

• Occurrence of biopsy-proven acute rejection necessitating rejection treatment

  At month 24 after randomization

• Acute AMR score in a protocol biopsy

  At month 24 after randomization

• Chronic AMR score in a protocol biopsy

  At month 24 after randomization

Study Arms (2)

Placebo (NaCl solution)

PLACEBO COMPARATOR

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

Bortezomib (Velcade®)

ACTIVE COMPARATOR

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

Interventions

Bortezomib DRUG

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.

Also known as: Velcade®

Bortezomib (Velcade®)

Placebo DRUG

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.

Also known as: NaCl solution

Placebo (NaCl solution)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Medical University of Vienna: lead
• Medical University Innsbruck: collaborator

Study Sites (1)

Medical University of Vienna, Department of Nephrology and Dialysis

Vienna, Vienna, 1090, Austria

Location

Related Publications (15)

• Colvin RB. Antibody-mediated renal allograft rejection: diagnosis and pathogenesis. J Am Soc Nephrol. 2007 Apr;18(4):1046-56. doi: 10.1681/ASN.2007010073. Epub 2007 Mar 14.

  PMID: 17360947 BACKGROUND

• Sis B, Mengel M, Haas M, Colvin RB, Halloran PF, Racusen LC, Solez K, Baldwin WM 3rd, Bracamonte ER, Broecker V, Cosio F, Demetris AJ, Drachenberg C, Einecke G, Gloor J, Glotz D, Kraus E, Legendre C, Liapis H, Mannon RB, Nankivell BJ, Nickeleit V, Papadimitriou JC, Randhawa P, Regele H, Renaudin K, Rodriguez ER, Seron D, Seshan S, Suthanthiran M, Wasowska BA, Zachary A, Zeevi A. Banff '09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups. Am J Transplant. 2010 Mar;10(3):464-71. doi: 10.1111/j.1600-6143.2009.02987.x. Epub 2010 Jan 29.

  PMID: 20121738 BACKGROUND

• Mauiyyedi S, Pelle PD, Saidman S, Collins AB, Pascual M, Tolkoff-Rubin NE, Williams WW, Cosimi AB, Schneeberger EE, Colvin RB. Chronic humoral rejection: identification of antibody-mediated chronic renal allograft rejection by C4d deposits in peritubular capillaries. J Am Soc Nephrol. 2001 Mar;12(3):574-582. doi: 10.1681/ASN.V123574.

  PMID: 11181806 BACKGROUND

• Einecke G, Sis B, Reeve J, Mengel M, Campbell PM, Hidalgo LG, Kaplan B, Halloran PF. Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure. Am J Transplant. 2009 Nov;9(11):2520-31. doi: 10.1111/j.1600-6143.2009.02799.x.

  PMID: 19843030 BACKGROUND

• Bohmig GA, Wahrmann M, Regele H, Exner M, Robl B, Derfler K, Soliman T, Bauer P, Mullner M, Druml W. Immunoadsorption in severe C4d-positive acute kidney allograft rejection: a randomized controlled trial. Am J Transplant. 2007 Jan;7(1):117-21. doi: 10.1111/j.1600-6143.2006.01613.x. Epub 2006 Nov 15.

  PMID: 17109725 BACKGROUND

• Vo AA, Lukovsky M, Toyoda M, Wang J, Reinsmoen NL, Lai CH, Peng A, Villicana R, Jordan SC. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Engl J Med. 2008 Jul 17;359(3):242-51. doi: 10.1056/NEJMoa0707894.

  PMID: 18635429 BACKGROUND

• Schwarz C, Regele H, Huttary N, Wahrmann M, Exner M, Nagy-Bojarsky K, Kletzmayr J, Horl WH, Bohmig GA. Rescue therapy with tacrolimus and mycophenolate mofetil does not prevent deterioration of graft function in C4d-positive chronic allograft nephropathy. Wien Klin Wochenschr. 2006 Jul;118(13-14):397-404. doi: 10.1007/s00508-006-0531-3.

  PMID: 16865644 BACKGROUND

• Schwaiger E, Regele H, Wahrmann M, Werzowa J, Haidbauer B, Schmidt A, Bohmig GA. Bortezomib for the treatment of chronic antibody-mediated kidney allograft rejection: a case report. Clin Transpl. 2010:391-6.

  PMID: 21696056 BACKGROUND

• Lachmann N, Terasaki PI, Budde K, Liefeldt L, Kahl A, Reinke P, Pratschke J, Rudolph B, Schmidt D, Salama A, Schonemann C. Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation. 2009 May 27;87(10):1505-13. doi: 10.1097/TP.0b013e3181a44206.

  PMID: 19461487 BACKGROUND

• Hidalgo LG, Campbell PM, Sis B, Einecke G, Mengel M, Chang J, Sellares J, Reeve J, Halloran PF. De novo donor-specific antibody at the time of kidney transplant biopsy associates with microvascular pathology and late graft failure. Am J Transplant. 2009 Nov;9(11):2532-41. doi: 10.1111/j.1600-6143.2009.02800.x.

  PMID: 19843031 BACKGROUND

• Rule AD, Larson TS, Bergstralh EJ, Slezak JM, Jacobsen SJ, Cosio FG. Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease. Ann Intern Med. 2004 Dec 21;141(12):929-37. doi: 10.7326/0003-4819-141-12-200412210-00009.

  PMID: 15611490 BACKGROUND

• DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med. 1994 Jul 15-30;13(13-14):1341-52; discussion 1353-6. doi: 10.1002/sim.4780131308.

  PMID: 7973215 BACKGROUND

• Loupy A, Aubert O, Orandi BJ, Naesens M, Bouatou Y, Raynaud M, Divard G, Jackson AM, Viglietti D, Giral M, Kamar N, Thaunat O, Morelon E, Delahousse M, Kuypers D, Hertig A, Rondeau E, Bailly E, Eskandary F, Bohmig G, Gupta G, Glotz D, Legendre C, Montgomery RA, Stegall MD, Empana JP, Jouven X, Segev DL, Lefaucheur C. Prediction system for risk of allograft loss in patients receiving kidney transplants: international derivation and validation study. BMJ. 2019 Sep 17;366:l4923. doi: 10.1136/bmj.l4923.

  PMID: 31530561 DERIVED

• Eskandary F, Bond G, Regele H, Kozakowski N, Kikic Z, Wahrmann M, Haslacher H, Oberbauer R, Ramassar V, Halloran P, Bohmig GA. Late Antibody-Mediated Rejection in a Large Prospective Cross-Sectional Study of Kidney Allograft Recipients--Preliminary Results of the Screening Phase of the BORTEJECT Trial. Clin Transpl. 2014:189-95.

  PMID: 26281144 DERIVED

• Eskandary F, Bond G, Schwaiger E, Kikic Z, Winzer C, Wahrmann M, Marinova L, Haslacher H, Regele H, Oberbauer R, Bohmig GA. Bortezomib in late antibody-mediated kidney transplant rejection (BORTEJECT Study): study protocol for a randomized controlled trial. Trials. 2014 Apr 3;15:107. doi: 10.1186/1745-6215-15-107.

  PMID: 24708575 DERIVED

MeSH Terms

Interventions

Bortezomib; Saline Solution

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Georg Böhmig, MD

  Medical University of Vienna, Department of Nephrology and Dialysis

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Farsad Eskandary, MD

Study Record Dates

• First Submitted: June 1, 2013
• First Posted: June 7, 2013
• Study Start: December 1, 2013
• Primary Completion: February 1, 2015
• Study Completion: February 28, 2017
• Last Updated: March 23, 2017

Record last verified: 2017-03

Locations

AU (1)