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

Phase 3

Completed

Conditions: Kidney Failure, Chronic

Interventions: Drug: Thymoglobulin
Drug: Daclizumab
Other: Plasmapheresis
Drug: Mycophenolate mofetil
Drug: Tacrolimus
Drug: Dexamethasone
Drug: Prednisone
Drug: Cytogam

Registration Number: NCT00275509

Lead Sponsor: Johns Hopkins University

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 56

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Thymoglobulin	Plasmapheresis	Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6.
Daclizumab	Plasmapheresis	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).
Thymoglobulin	Thymoglobulin	Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6.
Thymoglobulin	Dexamethasone	Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6.
Thymoglobulin	Mycophenolate mofetil	Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6.
Thymoglobulin	Tacrolimus	Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6.
Thymoglobulin	Cytogam	Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6.
Thymoglobulin	Prednisone	Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6.
Daclizumab	Tacrolimus	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).
Daclizumab	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).
Daclizumab	Mycophenolate mofetil	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).
Daclizumab	Dexamethasone	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).
Daclizumab	Prednisone	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).
Daclizumab	Cytogam	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).

Primary Outcome Measures

Name	Time	Method
6-month Cumulative Rejection Incidence (Either CMR, AMR or Both)	Up to 6 months	Biopsy shows evidence of either AMR or CMR or evidence both.
6-month Acute Antibody-mediated Rejection Rate (AMR)	Up to 6 months	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.
6-month Acute Cellular-mediated Rejection Rate (CMR)	Up to 6 months	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).