Kidney Failure, Chronic
Conditions
Keywords
kidney, transplantation, positive crossmatch, antibody mediated rejection, rejection, induction, therapy, trial
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.
Interventions
DRUGThymoglobulin
DRUGDaclizumab
OTHERPlasmapheresis
Following each plasmapheresis session, 100 mg/kg of Cytogam (CMVIg) (Cytogam, CSL Behring, King of Prussia, PA) was administered
DRUGMycophenolate mofetil
2 gm/day. Standard of care
DRUGTacrolimus
To achieve serum level of 8-10 ng/ml.
DRUGDexamethasone
100 mg intra-operatively, and 25 mg every 6h post-operatively for six doses
DRUGPrednisone
Taper over three months to 5 mg daily
DRUGCytogam
Following each plasmapheresis session, 100 mg/kg of Cytogam (CMVIg) (Cytogam, CSL Behring, King of Prussia, PA) was administered
Sponsors
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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 Cumulative Rejection Incidence (Either CMR, AMR or Both) | Up to 6 months | Biopsy shows evidence of either AMR or CMR or evidence both. |
Countries
United States
Participant flow
Recruitment details
A total of 207 participant were assessed for eligibility. Excluded (n=151) Not meeting inclusion criteria (n=115) Declined to participate (n=2) Did not reach transplant prior to end of study (n=34). A total of 56 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Tymoglobulin Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6 | 30 |
| 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). | 26 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | graft thrombosis, post-operative day #8 | 0 | 1 |
Baseline characteristics
| Characteristic | Tymoglobulin | Daclizumab | Total |
|---|---|---|---|
| Age, Continuous | 48.2 years STANDARD_DEVIATION 10.6 | 46.5 years STANDARD_DEVIATION 15.4 | 47.4 years STANDARD_DEVIATION 13 |
| Region of Enrollment United States | 30 participants | 26 participants | 56 participants |
| Sex: Female, Male Female | 19 Participants | 19 Participants | 38 Participants |
| Sex: Female, Male Male | 11 Participants | 7 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 30 | 2 / 26 |
| other Total, other adverse events | 19 / 30 | 20 / 26 |
| serious Total, serious adverse events | 6 / 30 | 9 / 26 |
Outcome results
Primary
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.
Time frame: Up to 6 months
Population: One patient in the Thymoglobulin arm died on post-operative day #8, prior to undergoing a biopsy. There were other deaths in the study however there were incidences of CMR, AMR or both prior to death.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tymoglobulin | 6-month Acute Antibody-mediated Rejection Rate (AMR) | 17 Participants |
| Daclizumab | 6-month Acute Antibody-mediated Rejection Rate (AMR) | 16 Participants |
Primary
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).
Time frame: Up to 6 months
Population: One patient in the Thymoglobulin arm died on post-operative day #8, prior to undergoing a biopsy. There were other deaths in the study however there were incidences of CMR, AMR or both prior to death.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tymoglobulin | 6-month Acute Cellular-mediated Rejection Rate (CMR) | 14 Participants |
| Daclizumab | 6-month Acute Cellular-mediated Rejection Rate (CMR) | 20 Participants |
Primary
6-month Cumulative Rejection Incidence (Either CMR, AMR or Both)
Biopsy shows evidence of either AMR or CMR or evidence both.
Time frame: Up to 6 months
Population: One patient in the Thymoglobulin arm died on post-operative day #8, prior to undergoing a biopsy. There were other deaths in the study however there were incidences of CMR, AMR or both prior to death.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tymoglobulin | 6-month Cumulative Rejection Incidence (Either CMR, AMR or Both) | 21 Participants |
| Daclizumab | 6-month Cumulative Rejection Incidence (Either CMR, AMR or Both) | 23 Participants |