Randomized Trial of Induction Therapies in High Immunological Risk Kidney Transplant Recipients

This study has been completed.
Sponsor:
Collaborators:
Millennium Pharmaceuticals, Inc.
Genzyme, a Sanofi Company
Information provided by (Responsible Party):
E. Steve Woodle, University of Cincinnati
ClinicalTrials.gov Identifier:
NCT00782821
First received: October 29, 2008
Last updated: December 14, 2015
Last verified: December 2015
  Purpose
The purpose of this research study is to find out the effects of adding B lymphocyte modulating agents in patients at risk for rejection receiving an anti-rejection (immunosuppressive) regimen of Thymoglobulin® induction with Prograf®, Cellcept® and corticosteroid therapy.

Condition Intervention Phase
Kidney Transplantation
Drug: Rabbit Antithymocyte Globulin
Drug: Velcade
Drug: Rituxan
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Targeted Therapy for High Immunologic Risk Renal Transplant Recipients: A Prospective, Randomized, Open-Label Pilot Study of B-Cell Depleting Therapy in Combination With Anti-Thymocyte Globulin [Rabbit] (Thymoglobulin®, Genzyme), Tacrolimus (Prograf®, Astellas), Mycophenolate Mofetil (CellCept®, Roche) and Corticosteroid Minimization

Resource links provided by NLM:


Further study details as provided by University of Cincinnati:

Primary Outcome Measures:
  • Incidence of Acute Rejection (Banff '97) or Antibody Mediated Rejection [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    Antibody mediated rejection demonstrated to be due to, atleast in part, to anti-donor antibody at 6 months by Banff 97' criteria.

    Acute rejection IA - cases with significant interstitial infiltration (>25% of parenchyma affected) and foci of moderate tubulitis (>4 mononuclear cells/tubular cross section or group of 10 tubular cells).

    IB - cases with significant interstitial infiltration (>25% of parenchyma affected) and foci of severe tubulitis (>10 mononuclear cells/tubular cross section or group of 10 tubular cells) IIA - cases with mild to moderate intimal arteritis (v1) IIB - cases with server intimal arteritis comprising >25% of the luminal area (v2) III - case with transmural arteritis and/or arterial fibrinoid change and necrosis of medical smooth muscle cells (v3 with accompanying lymphoctic inflammation)



Secondary Outcome Measures:
  • Antibody-mediated Rejection by Banff '97 Criteria (Updated 2005) [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    Antibody mediated rejection demonstrated to be due to, atleast in part, to anti-donor antibody at 6 months by Banff 97' criteria. Rejection due, at least in part, to documented anti-donor antibody ('suspicious for' if antibody not demonstrated); may coincide with categories 3, 4 and 5.

    Grade I. ATN-like - C4d+, minimal inflammation Grade II. Capillary- margination and/or thromboses, C4d+ Grade III. Arterial - v3, C4d+


  • Acute Cellular Rejection by Banff '97 Criteria (Updated 2005) [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    Acute cellular rejection IA - cases with significant interstitial infiltration (>25% of parenchyma affected) and foci of moderate tubulitis (>4 mononuclear cells/tubular cross section or group of 10 tubular cells).

    IB - cases with significant interstitial infiltration (>25% of parenchyma affected) and foci of severe tubulitis (>10 mononuclear cells/tubular cross section or group of 10 tubular cells) IIA - cases with mild to moderate intimal arteritis (v1) IIB - cases with server intimal arteritis comprising >25% of the luminal area (v2) III - case with transmural arteritis and/or arterial fibrinoid change and necrosis of medical smooth muscle cells (v3 with accompanying lymphoctic inflammation)


  • Patient Survival at 12 Months [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    Patient was still alive 12 months post study enrollment.

  • Patient Allograft Survival at 12 Months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Patient's allograft was still functioning at 12 months post study enrollment


Enrollment: 40
Study Start Date: September 2008
Study Completion Date: March 2013
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Rabbit Antithymocyte Globulin (rATG)
Rabbit Antithymocyte Globulin (rATG) 1.5mg/kg per dose x 6 doses rATG was administered on post-op day 0, 2, 4, 6, 8 and 10.
Drug: Rabbit Antithymocyte Globulin
rATG will be given 1.5mg/kg intravenous (IV) per dose.
Other Names:
  • Thymoglobulin
  • rATG
Experimental: RATG/Rituxan
Rabbit Antithymocyte Globulin (rATG)/Rituxan 1.5mg/kg per dose x 5 doses of rATG. 375mg/m2 x 1 dose of rituxan. rATG was administered on post-op day 0, 2, 4, 6 and 8. Rituxan was given on post-op day 1.
Drug: Rabbit Antithymocyte Globulin
rATG will be given 1.5mg/kg intravenous (IV) per dose.
Other Names:
  • Thymoglobulin
  • rATG
Drug: Rituxan
Given via IV per group assignment.
Other Name: Rituximab
Experimental: RATG/Velcade
Rabbit Antithymocyte Globulin (rATG) /Velcade 1.5mg/kg per dose x 5 doses of rATG. 1.3mg/m2 per dose x 4 doses of velcade. rATG was administered on post-op day 0, 2, 4, and 6. Velcade was administered on post-op day 0, 3, 7 and 10.
Drug: Rabbit Antithymocyte Globulin
rATG will be given 1.5mg/kg intravenous (IV) per dose.
Other Names:
  • Thymoglobulin
  • rATG
Drug: Velcade
Velcade will be given 1.3mg/m2 via intravenous push (IVP) per dose.
Other Name: bortezomib
Experimental: RATG/Rituxan/Velcade

Rabbit Antithymocyte Globulin (RATG) / Rituxan / Velcade 1.5mg/kg per dose x 4 doses of rATG. 200mg/m2 for 1 dose of rituxan. 1.3mg/m2 per dose x 4 doses of velcade.

rATG was administered on post-op day 0, 2, 4, and 6. Velcade was administered on post-op day 0, 3, 7 and 10. Rituxan was given on post-op day 1.

Drug: Rabbit Antithymocyte Globulin
rATG will be given 1.5mg/kg intravenous (IV) per dose.
Other Names:
  • Thymoglobulin
  • rATG
Drug: Velcade
Velcade will be given 1.3mg/m2 via intravenous push (IVP) per dose.
Other Name: bortezomib
Drug: Rituxan
Given via IV per group assignment.
Other Name: Rituximab

Detailed Description:
Optimal induction regimens for patients at high risk for antibody and/or cell-mediated rejection have not been established. This pilot, prospective, randomized study evaluated addition of B cell/plasma cell-targeting agents to T cell-based induction with rabbit antithymocyte globulin (rATG) in high immunologic risk renal transplant recipients. Patients were randomized to induction with rATG, rATGþrituximab, rATGþbortezomib or rATGþrituximabþbortezomib.
  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

Each patient must meet all of the following inclusion criteria to be enrolled in the study:

  • Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
  • Patient is between the 18 and 65 years of age, inclusive.
  • Patient is considered high risk for acute rejection based on any one of the following:

    • Patient has a current Cytotoxic PRA≥ 20% or a peak Cytotoxic PRA ≥50%
    • Patient has a T or B-cell positive crossmatch (by flow cytometry) with confirmed donor-specific antibodies on solid-phase assay.
    • Historical positive serologic or cytotoxic crossmatch or DSA to donor
    • Prior allograft loss with a history of more than one acute rejection episode.
  • Female subject is either postmenopausal for at least 1 year prior to initiation of study treatment, is surgically sterilized, or if of childbearing potential, agrees to practice 2 effective methods of contraception from the time of signing the informed consent form through 30 days after the last dose of bortezomib, or agrees to completely abstain from heterosexual intercourse. Women of childbearing potential must have a negative serum pregnancy test within the last 48 hours prior to receiving study medication.
  • Male subjects, even if surgically sterilized (i.e. status post-vasectomy) must agree to 1 of the following: practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, or completely abstain from heterosexual intercourse.
  • Patient must have no known contraindications to treatment with bortezomib, rituximab, or thymoglobulin.

Exclusion Criteria

  • Patients that have previously received or are receiving an organ transplant other than kidney.
  • Patient who lost a previous allograft due to recurrence of disease
  • Patient is receiving a HLA identical living related kidney transplant
  • History of severe allergic or anaphylactic reactions to humanized or murine monoclonal or polyclonal antibodies
  • Patients with an absolute neutrophil count of < 1,000/mm3 or platelet count < 100,000/mm3within 30 days of consent.
  • Patient has Grade 2 peripheral neuropathy by CTCAE criteria within 14 days before enrollment.
  • Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (see section 9.3), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any abnormality on ECG performed within 30 days of consent has to be documented by the investigator or the patient's transplant nephrologist as not medically relevant.
  • Patients who are anti-HIV-positive, or HBsAg-positive or Anti-HCV positive on testing performed within one year of consent.
  • Diagnosed or treated for malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
  • Patients with current or recent severe systemic infections within the 2 weeks prior to initiation of study treatment.
  • Receipt of a live vaccine within 4 weeks prior to initiation of study treatment.
  • Use of other investigational drugs within 30 days or 5 half-lives prior to initiation of study treatment, whichever is longer
  • Evidence of severe liver disease by medical history or physical exam with abnormal liver profile (aspartate aminotransferase [AST], alanine aminotransferase [ALT] or total bilirubin > 1.5 times upper limit of normal [ULN]) on testing performed within 30 days of consent.
  • Pregnant or nursing (lactating) women and women who might become pregnant during the study. Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum -human chorionic gonadotropin pregnancy test result within the last 48 hours prior to receiving study medication. Pregnancy testing is not required for post-menopausal or surgically sterilized women.
  • EBV serologic mismatch (i.e. EBV+ donor transplanted to EBV- recipient)
  • CMV serologic mismatch (i.e. CMV+ donor transplanted to CMV- recipient)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00782821

Locations
United States, Ohio
The Christ Hospital
Cincinnati, Ohio, United States, 45202
The University Hospital
Cincinnati, Ohio, United States, 45219
Sponsors and Collaborators
University of Cincinnati
Millennium Pharmaceuticals, Inc.
Genzyme, a Sanofi Company
Investigators
Principal Investigator: E. Steve Woodle, MD University of Cincinnati
  More Information

No publications provided

Responsible Party: E. Steve Woodle, MD, FACS, University of Cincinnati
ClinicalTrials.gov Identifier: NCT00782821     History of Changes
Other Study ID Numbers: X05274 
Study First Received: October 29, 2008
Results First Received: October 20, 2015
Last Updated: December 14, 2015
Health Authority: United States: Institutional Review Board

Keywords provided by University of Cincinnati:
Kidney
Renal
Rejection
High risk
Induction
Immunology
Transplantation
B Cell
Allograft
Desensitization

Additional relevant MeSH terms:
Antilymphocyte Serum
Bortezomib
Rituximab
Antineoplastic Agents
Antirheumatic Agents
Immunologic Factors
Immunosuppressive Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on February 07, 2016