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

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00275509
• Collaborator: (none)
• Enrollment: 56
• Location: 1
• Arms: 2
• Actual Duration (Months): 41
• Patients Per Site Per Month: 1.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Kidney Failure, Chronic	Drug: Thymoglobulin; Drug: Daclizumab; Other: Plasmapheresis; Drug: Mycophenolate mofetil; Drug: Tacrolimus; Drug: Dexamethasone; Drug: Prednisone; Drug: Cytogam	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 56 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: 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
• Actual Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Jun 1, 2010
• Actual Study Completion Date: Jun 1, 2010

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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).

2. 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.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Johns Hopkins University, School of Medicine	Baltimore	Maryland	United States	21205

Sponsors and Collaborators

• 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

Study Documents (Full-Text)

None provided.

More Information

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.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT00275509
• Other Study ID Numbers: IRB00078055
• First Posted: Jan 12, 2006
• Last Update Posted: Jan 18, 2018
• Last Verified: Dec 1, 2017

• Keywords provided by Johns Hopkins University: kidney; transplantation; positive crossmatch; antibody mediated rejection; rejection; induction; therapy; trial
• Additional relevant MeSH terms: Renal Insufficiency; Kidney Failure, Chronic; Mycophenolic Acid; Dexamethasone; Prednisone; Tacrolimus; Thymoglobulin; Daclizumab

Study Results

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.

Arm/Group Title	Thymoglobulin	Daclizumab
Arm/Group Description	Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6.	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).
Period Title: Overall Study
STARTED	30	26
COMPLETED	30	25
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Tymoglobulin	Daclizumab	Total
Arm/Group Description	Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6	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).	Total of all reporting groups
Overall Participants	30	26	56
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.2 (10.6)	46.5 (15.4)	47.4 (13.0)
Sex: Female, Male (Count of Participants)
Female	19 63.3%	19 73.1%	38 67.9%
Male	11 36.7%	7 26.9%	18 32.1%
Region of Enrollment (participants) [Number]
United States	30 100%	26 100%	56 100%

Outcome Measures

1. Primary Outcome

Title	6-month Acute Cellular-mediated Rejection Rate (CMR)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Tymoglobulin	Daclizumab
Arm/Group Description	Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6	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).
Measure Participants	29	26
Count of Participants [Participants]	14 46.7%	20 76.9%

2. Primary Outcome

Title	6-month Acute Antibody-mediated Rejection Rate (AMR)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Tymoglobulin	Daclizumab
Arm/Group Description	Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6	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).
Measure Participants	29	26
Count of Participants [Participants]	17 56.7%	16 61.5%

3. Primary Outcome

Title	6-month Cumulative Rejection Incidence (Either CMR, AMR or Both)
Description	Biopsy shows evidence of either AMR or CMR or evidence both.
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

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/Group Title	Tymoglobulin	Daclizumab
Arm/Group Description	Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6	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).
Measure Participants	29	26
Count of Participants [Participants]	21 70%	23 88.5%

Adverse Events

Time Frame	One year from date of transplant
Adverse Event Reporting Description	occasional assessment/testing
Arm/Group Title	Tymoglobulin		Daclizumab
Arm/Group Description	Thymoglobulin was administered as 1.5 mg/kg prior to reperfusion followed by 6 post-operative doses on days 1 through 6		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).
All Cause Mortality
	Tymoglobulin		Daclizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/30 (10%)		2/26 (7.7%)
Serious Adverse Events
	Tymoglobulin		Daclizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/30 (20%)		9/26 (34.6%)
Cardiac disorders
Cardiovascular disease	1/30 (3.3%)	1	0/26 (0%)	0
Gastrointestinal disorders
Perforated gastric ulcer	1/30 (3.3%)	1	0/26 (0%)	0
General disorders
Fever	1/30 (3.3%)	1	0/26 (0%)	0
Pancreatitis	1/30 (3.3%)	1	0/26 (0%)	0
delirium tremens seizure	0/30 (0%)	0	1/26 (3.8%)	2
Infections and infestations
H1N1 flu	0/30 (0%)	0	1/26 (3.8%)	1
Respiratory syncytial virus (RSV) Pneumonia	0/30 (0%)	0	1/26 (3.8%)	1
Septic shock	0/30 (0%)	0	1/26 (3.8%)	1
Cytomegalovirus (CMV)	1/30 (3.3%)	1	0/26 (0%)	0
Pneumonia	1/30 (3.3%)	1	1/26 (3.8%)	1
Histoplasmosis	1/30 (3.3%)	1	3/26 (11.5%)	3
Polyoma virus (BK)	1/30 (3.3%)	1	1/26 (3.8%)	1
Urinary tract infection (UTI)	1/30 (3.3%)	1	1/26 (3.8%)	1
Product Issues
Rejection	1/30 (3.3%)	2	0/26 (0%)	0
Renal and urinary disorders
Allograft loss	2/30 (6.7%)	2	4/26 (15.4%)	4
Recurrent focal segmental glomerulosclerosis	0/30 (0%)	0	1/26 (3.8%)	1
Surgical and medical procedures
intra-thoracic vascular injury during placement of a central venous catheter	1/30 (3.3%)	1	0/26 (0%)	0
Other (Not Including Serious) Adverse Events
	Tymoglobulin		Daclizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/30 (63.3%)		20/26 (76.9%)
Blood and lymphatic system disorders
Leukocytosis	0/30 (0%)	0	1/26 (3.8%)	1
Gastrointestinal disorders
Esophagitis	0/30 (0%)	0	1/26 (3.8%)	1
General disorders
Fever	1/30 (3.3%)	1	0/26 (0%)	0
Rash	1/30 (3.3%)	1	0/26 (0%)	0
Infections and infestations
Urinary Tract Infection	12/30 (40%)	17	9/26 (34.6%)	18
Blood stream infection	1/30 (3.3%)	1	3/26 (11.5%)	3
C-difficile infection	1/30 (3.3%)	1	2/26 (7.7%)	2
Cellulitis	0/30 (0%)	0	1/26 (3.8%)	1
Central line-associated bloodstream infection (CLABSI)	1/30 (3.3%)	1	2/26 (7.7%)	2
Infection of disc space	0/30 (0%)	0	1/26 (3.8%)	1
Intra-abdominal infection	5/30 (16.7%)	6	2/26 (7.7%)	2
Polyoma virus (BK)	2/30 (6.7%)	2	1/26 (3.8%)	1
Surgical site infection	3/30 (10%)	3	5/26 (19.2%)	6
Upper respiratory infection (URI)	1/30 (3.3%)	4	2/26 (7.7%)	2
Vancomycin-resistant enterococci (VRE)	1/30 (3.3%)	1	1/26 (3.8%)	1
Wound infection	2/30 (6.7%)	2	0/26 (0%)	0
Bile infection	1/30 (3.3%)	1	0/26 (0%)	0
Renal and urinary disorders
Increase in creatinine	1/30 (3.3%)	1	0/26 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.