Induction Therapy Study in Live Donor Kidney Transplant Recipients With a Positive Crossmatch

Open Label Randomized Study of Thymoglobulin Versus Daclizumab Induction Therapies for the Reduction of Acute Rejection in Live Donor Kidney Transplant Recipients With a Positive Crossmatch

The purpose of this study is to determine whether the anti-T cell antibody, Thymoglobulin is a more effective induction medication than the anti-IL-2R inhibitor daclizumab, in kidney transplant recipients who have a positive crossmatch with their live donor.

Study Overview

• Status: Completed
• Conditions: Kidney Failure, Chronic
• Intervention / Treatment: Drug: Thymoglobulin; Drug: Daclizumab; Other: Plasmapheresis; Drug: Mycophenolate mofetil; Drug: Tacrolimus; Drug: Dexamethasone; Drug: Prednisone; Drug: Cytogam

Detailed Description

Kidney transplantation is widely recognized as the optimal therapy for the management of end-stage renal disease. Presently, the deceased donor kidney waiting list has expanded disproportionately with the number of transplant procedures that are performed in the United States. To further compound this problem, as many as 1/3 of the patients on this list are highly sensitized against a broad range of potential donors.

In order to address this problem, we developed an antibody depletion protocol that permits transplantation in patients who have a positive crossmatch with their live donor. The protocol consists of standard immunosuppressant therapy, plasmapheresis, and intravenous immunoglobulin infusion. We have successfully performed transplantation in over 100 such patients with low complication rates.

Because these patients have been exposed to their donor's human leukocyte antigen (HLA) they are at high risk for both acute cellular and acute antibody-mediated rejection. This intent of this prospective, randomized, open-label trial is to determine whether induction therapy (i.e. therapy given at the time of transplantation for prophylaxis) with Thymoglobulin is associated with a lower 6-month incidence of acute cellular and antibody-mediated rejection than with our standard therapy, daclizumab.

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • The Johns Hopkins University, School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult (18 years or older)
• End-stage renal disease
• Identified to have positive lymphocytotoxic crossmatch or flow cytometric crossmatch with live donor

Exclusion Criteria:

• Deceased donor recipients
• Pregnancy
• Active infection
• History of cancer within the past two years (with the exception of non-melanomatous skin cancer)
• History of heparin induced thrombocytopenia
• Medical contraindications to transplant procedure

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Thymoglobulin; Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6.	Drug: Thymoglobulin; Other: Plasmapheresis; Following each plasmapheresis session, 100 mg/kg of Cytogam (CMVIg) (Cytogam, CSL Behring, King of Prussia, PA) was administered; Drug: Mycophenolate mofetil; 2 gm/day. Standard of care; Drug: Tacrolimus; To achieve serum level of 8-10 ng/ml.; Drug: Dexamethasone; 100 mg intra-operatively, and 25 mg every 6h post-operatively for six doses; Drug: Prednisone; Taper over three months to 5 mg daily; Drug: Cytogam; Following each plasmapheresis session, 100 mg/kg of Cytogam (CMVIg) (Cytogam, CSL Behring, King of Prussia, PA) was administered
Experimental: Daclizumab; Daclizumab was administered as 2 mg/kg prior to reperfusion followed by 1 mg/kg every other week for 8 weeks post-operatively (4 post-operative doses).	Drug: Daclizumab; Other: Plasmapheresis; Following each plasmapheresis session, 100 mg/kg of Cytogam (CMVIg) (Cytogam, CSL Behring, King of Prussia, PA) was administered; Drug: Mycophenolate mofetil; 2 gm/day. Standard of care; Drug: Tacrolimus; To achieve serum level of 8-10 ng/ml.; Drug: Dexamethasone; 100 mg intra-operatively, and 25 mg every 6h post-operatively for six doses; Drug: Prednisone; Taper over three months to 5 mg daily; Drug: Cytogam; Following each plasmapheresis session, 100 mg/kg of Cytogam (CMVIg) (Cytogam, CSL Behring, King of Prussia, PA) was administered

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6-month Acute Cellular-mediated Rejection Rate (CMR)	Per 2007 international Banff Classification Criteria, CMR 1A was diagnosed on biopsies displaying significant interstitial infiltration (>25% of parenchyma affected, i2 or i3) and foci of moderate tubulitis (t2). CMR IB was diagnosed in cases with significant interstitial infiltration (>25% of parenchyma affected, i2 or i3) and foci of severe tubulitis (t3). CMR IIA were cases with mild-to-moderate intimal arteritis (v1), while CMR IIB were those with severe intimal arteritis comprising >25% of the luminal area (v2). CMR III were those cases with transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation (v3).	Up to 6 months
6-month Acute Antibody-mediated Rejection Rate (AMR)	A diagnosis of AMR was based on the 2013 international Banff Classification Criteria and is defined as the presence of circulating donor-specific antibody (DSA) and either: 1) peritubular capillary staining of C4d and at least one of the following: peritubular capillaritis (ptc) score>0, glomerulitis (g) score>0, acute thrombotic microangiopathy (TMA) in the absence of any other cause, or other features consistent with AMR (endothelial injury, fibrin thrombi, microinfarctions, interstitial hemorrhage), or 2) absence of capillary staining of C4d and the presence of ptc>0 and g>0 or ptc>0 or g>0 and acute TMA, in the absence of any other cause of TMA.	Up to 6 months
6-month Cumulative Rejection Incidence (Either CMR, AMR or Both)	Biopsy shows evidence of either AMR or CMR or evidence both.	Up to 6 months

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Investigators: Principal Investigator: Robert A Montgomery, M.D., Ph.D., Johns Hopkins University , SOM; Study Director: Christopher E Simpkins, M.D., Johns Hopkins University, SOM

Publications and helpful links

General Publications

• Haas M, Sis B, Racusen LC, Solez K, Glotz D, Colvin RB, Castro MC, David DS, David-Neto E, Bagnasco SM, Cendales LC, Cornell LD, Demetris AJ, Drachenberg CB, Farver CF, Farris AB 3rd, Gibson IW, Kraus E, Liapis H, Loupy A, Nickeleit V, Randhawa P, Rodriguez ER, Rush D, Smith RN, Tan CD, Wallace WD, Mengel M; Banff meeting report writing committee. Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant. 2014 Feb;14(2):272-83. doi: 10.1111/ajt.12590. Erratum In: Am J Transplant. 2015 Oct;15(10):2784. Rangel, Erika [corrected to Rangel, Erika B].
• Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, Halloran PF, Baldwin W, Banfi G, Collins AB, Cosio F, David DS, Drachenberg C, Einecke G, Fogo AB, Gibson IW, Glotz D, Iskandar SS, Kraus E, Lerut E, Mannon RB, Mihatsch M, Nankivell BJ, Nickeleit V, Papadimitriou JC, Randhawa P, Regele H, Renaudin K, Roberts I, Seron D, Smith RN, Valente M. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. 2008 Apr;8(4):753-60. doi: 10.1111/j.1600-6143.2008.02159.x. Epub 2008 Feb 19.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2007
• Primary Completion (Actual): June 1, 2010
• Study Completion (Actual): June 1, 2010

Study Registration Dates

• First Submitted: January 10, 2006
• First Submitted That Met QC Criteria: January 10, 2006
• First Posted (Estimate): January 12, 2006

Study Record Updates

• Last Update Posted (Actual): January 18, 2018
• Last Update Submitted That Met QC Criteria: December 19, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Keywords: rejection; transplantation; trial; kidney; therapy; induction; positive crossmatch; antibody mediated rejection
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Renal Insufficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Dexamethasone; Prednisone; Tacrolimus; Mycophenolic Acid; Thymoglobulin; Daclizumab
• Other Study ID Numbers: IRB00078055