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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Kidney Failure, Chronic

Intervention / Treatment
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* Drug: Thymoglobulin
* Drug: Daclizumab
* Other: Plasmapheresis
* Drug: Mycophenolate mofetil
* Drug: Tacrolimus
* Drug: Dexamethasone
* Drug: Prednisone
* Drug: Cytogam


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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kidney, transplantation, positive crossmatch, antibody mediated rejection, rejection, induction, therapy, trial