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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Thymoglobulin | Experimental | Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6. |
|
| Daclizumab | Experimental | 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). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Thymoglobulin | Drug |
| ||
| Daclizumab |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Robert A Montgomery, M.D., Ph.D. | Johns Hopkins University , SOM | Principal Investigator |
| Christopher E Simpkins, M.D. | Johns Hopkins University, SOM | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Johns Hopkins University, School of Medicine | Baltimore | Maryland | 21205 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24472190 | Background | 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. | |
| 18294345 |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Thymoglobulin | Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6. |
| FG001 | 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). |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Tymoglobulin | Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6 |
| BG001 | 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). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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). | 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. | Posted | Count of Participants | Participants | Up to 6 months |
|
One year from date of transplant
occasional assessment/testing
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Tymoglobulin | Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| intra-thoracic vascular injury during placement of a central venous catheter | Surgical and medical procedures | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Urinary Tract Infection | Infections and infestations | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Robert Montgomery, MD | New York University Langone Transplant Institute | 646-501-2418 | Robert.Montgomery@nyumc.org |
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| ID | Term |
|---|---|
| D007676 | Kidney Failure, Chronic |
| D012059 | Rejection, Psychology |
| ID | Term |
|---|---|
| D051436 | Renal Insufficiency, Chronic |
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
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| ID | Term |
|---|---|
| C512542 | thymoglobulin |
| D000077561 | Daclizumab |
| D010956 | Plasmapheresis |
| D009173 | Mycophenolic Acid |
| D016559 | Tacrolimus |
| D003907 | Dexamethasone |
| D011241 | Prednisone |
| C045781 | cytomegalovirus-specific hyperimmune globulin |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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|
| Plasmapheresis | Other | Following each plasmapheresis session, 100 mg/kg of Cytogam (CMVIg) (Cytogam, CSL Behring, King of Prussia, PA) was administered |
|
| Mycophenolate mofetil | Drug | 2 gm/day. Standard of care |
|
| Tacrolimus | Drug | To achieve serum level of 8-10 ng/ml. |
|
| Dexamethasone | Drug | 100 mg intra-operatively, and 25 mg every 6h post-operatively for six doses |
|
| Prednisone | Drug | Taper over three months to 5 mg daily |
|
| Cytogam | Drug | Following each plasmapheresis session, 100 mg/kg of Cytogam (CMVIg) (Cytogam, CSL Behring, King of Prussia, PA) was administered |
|
| Background |
| 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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Tymoglobulin |
Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6 |
| OG001 | 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). |
|
|
| 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. | 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. | Posted | Count of Participants | Participants | Up to 6 months |
|
|
|
| Primary | 6-month Cumulative Rejection Incidence (Either CMR, AMR or Both) | Biopsy shows evidence of either AMR or CMR or evidence both. | 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. | Posted | Count of Participants | Participants | Up to 6 months |
|
|
|
| 3 |
| 30 |
| 6 |
| 30 |
| 19 |
| 30 |
| EG001 | 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). | 2 | 26 | 9 | 26 | 20 | 26 |
| Allograft loss | Renal and urinary disorders | Non-systematic Assessment |
|
| Perforated gastric ulcer | Gastrointestinal disorders | Non-systematic Assessment |
|
| Cardiovascular disease | Cardiac disorders | Non-systematic Assessment |
|
| H1N1 flu | Infections and infestations | Non-systematic Assessment |
|
| Respiratory syncytial virus (RSV) Pneumonia | Infections and infestations | Non-systematic Assessment |
|
| Septic shock | Infections and infestations | Non-systematic Assessment |
|
| Recurrent focal segmental glomerulosclerosis | Renal and urinary disorders | Non-systematic Assessment |
|
| Cytomegalovirus (CMV) | Infections and infestations | Non-systematic Assessment |
|
| Fever | General disorders | Non-systematic Assessment |
|
| Pneumonia | Infections and infestations | Systematic Assessment |
|
| Histoplasmosis | Infections and infestations | Non-systematic Assessment |
|
| Pancreatitis | General disorders | Non-systematic Assessment |
|
| Rejection | Product Issues | Non-systematic Assessment |
|
| Polyoma virus (BK) | Infections and infestations | Non-systematic Assessment |
|
| Urinary tract infection (UTI) | Infections and infestations | Non-systematic Assessment |
|
| delirium tremens seizure | General disorders | Non-systematic Assessment |
|
| Blood stream infection | Infections and infestations | Non-systematic Assessment |
|
| C-difficile infection | Infections and infestations | Non-systematic Assessment |
|
| Cellulitis | Infections and infestations | Non-systematic Assessment |
|
| Central line-associated bloodstream infection (CLABSI) | Infections and infestations | Non-systematic Assessment |
|
| Esophagitis | Gastrointestinal disorders | Non-systematic Assessment |
|
| Infection of disc space | Infections and infestations | Non-systematic Assessment |
|
| Intra-abdominal infection | Infections and infestations | Non-systematic Assessment |
|
| Leukocytosis | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Polyoma virus (BK) | Infections and infestations | Non-systematic Assessment |
|
| Surgical site infection | Infections and infestations | Non-systematic Assessment |
|
| Upper respiratory infection (URI) | Infections and infestations | Non-systematic Assessment |
|
| Vancomycin-resistant enterococci (VRE) | Infections and infestations | Non-systematic Assessment |
|
| Fever | General disorders | Non-systematic Assessment |
|
| Rash | General disorders | Non-systematic Assessment |
|
| Wound infection | Infections and infestations | Non-systematic Assessment |
|
| Increase in creatinine | Renal and urinary disorders | Non-systematic Assessment |
|
| Bile infection | Infections and infestations | Non-systematic Assessment |
|
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| D052776 |
| Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012919 | Social Behavior |
| D001519 | Behavior |
| D007162 |
| Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D001781 | Blood Component Removal |
| D013812 | Therapeutics |
| D016060 | Sorption Detoxification |
| D005112 | Extracorporeal Circulation |
| D013514 | Surgical Procedures, Operative |
| D002208 | Caproates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
| D005227 | Fatty Acids |
| D008055 | Lipids |
| D018942 | Macrolides |
| D007783 | Lactones |
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D013259 | Steroids, Fluorinated |
| D011244 | Pregnadienediols |