Randomized Trial for Mixed Acute Rejection

• Sponsor: University of Cincinnati (Other)
• Overall Status: Completed
• CT.gov ID: NCT00771875
• Collaborator: (none)
• Enrollment: 30
• Locations: 2
• Arms: 3
• Duration (Months): 53.9
• Patients Per Site: 15
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study is being conducted to determine how safe and effective using an immune cell (b cell) depleting therapy and/or Thymoglobulin is in patients with a kidney transplant who are experiencing certain types of rejection.

Condition or Disease	Intervention/Treatment	Phase
Graft Rejection	Drug: Rabbit Antithymocyte Globulin (RATG); Drug: Rituximab; Drug: Bortezomib; Drug: Acetaminophen; Drug: Antihistamine; Drug: Methylprednisolone	Phase 2

Detailed Description

The purpose of the study is to determine safety and efficacy of treatment if mixed (cellular and antibody) mediated acute rejection with addition of B-cell depleting therapy to Thymoglobulin in kidney and simultaneous kidney pancreas allograft recipients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: B-Cell Targeted Therapy for Acute Renal Allograft Rejection With an Antibody Mediated Component: A Prospective, Randomized, Open-Label Study
• Study Start Date: Sep 1, 2008
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Rabbit Antithymocyte Globulin (RATG) Rabbit Antithymocyte Globulin (RATG) All patients will receive RATG (Thymoglobulin) dosed based on CD3 count. Patients will be redosed when the cluster of differentiation 3 (CD3) count is ≥ 25. Depending on rejection severity, Thymoglobulin will be given for a maximum of 7-14 days. CD3 levels will be monitored daily. 1.5mg/kg/day over 6 hrs with 1st dose (D1) and over 4 hours for each dose thereafter. (day 1 then when CD3 levels > 25 cells/mm3); Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care. Methylprednisolone 250 mg with 1st dose of Thymoglobulin. Methylprednisolone 125 mg on treatment day 2 subsequent corticosteroids per institution standard of care; following treatment, corticosteroid therapy will resume at the pre-rejection dose.	Drug: Rabbit Antithymocyte Globulin (RATG); All patients will receive Thymoglobulin dosed based on CD3 count. Patients will be redosed when the CD3 count is ≥ 25. Depending on rejection severity, Thymoglobulin will be given for a maximum of 7-14 days. CD3 levels will be monitored daily.; Other Names: thymoglobulin ; Drug: Rituximab; Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care.; Other Names: rituxan ; Drug: Bortezomib; Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.; Other Names: Velcade ; Drug: Acetaminophen; Patients will be premedicated with acetaminophen prior to dosing per institution standard of care.; Other Names: Tylenol ; Drug: Antihistamine; Patients will be premedicated with an antihistamine prior to dosing per institution standard of care.; Other Names: diphenhydramine ; Drug: Methylprednisolone; Methylprednisolone 250 mg with 1st dose of Thymoglobulin. Methylprednisolone 125 mg on treatment day 2 subsequent corticosteroids per institution standard of care; following treatment, corticosteroid therapy will resume at the pre-rejection dose.; Other Names: Medrol
Experimental: RATG/Rituximab Rabbit Antithymocyte Globulin (RATG) + Rituximab Subjects will be given 1.5mg/kg/day of RATG over 6 hrs with 1st dose (D1) and over 4 hours for each dose thereafter. (day 1 then when CD3 levels > 25 cells/mm3); Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care. Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care. Methylprednisolone 250 mg with 1st dose of Thymoglobulin. Methylprednisolone 125 mg on treatment day 2 subsequent corticosteroids per institution standard of care; following treatment, corticosteroid therapy will resume at the pre-rejection dose.	Drug: Rituximab; Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care.; Other Names: rituxan ; Drug: Acetaminophen; Patients will be premedicated with acetaminophen prior to dosing per institution standard of care.; Other Names: Tylenol ; Drug: Antihistamine; Patients will be premedicated with an antihistamine prior to dosing per institution standard of care.; Other Names: diphenhydramine ; Drug: Methylprednisolone; Methylprednisolone 250 mg with 1st dose of Thymoglobulin. Methylprednisolone 125 mg on treatment day 2 subsequent corticosteroids per institution standard of care; following treatment, corticosteroid therapy will resume at the pre-rejection dose.; Other Names: Medrol
Experimental: RATG/Bortezomib Rabbit Antithymocyte Globulin (RATG) + Bortezomib -Subjects will be given 1.5mg/kg/day of RATG over 6 hrs with 1st dose (D1) and over 4 hours for each dose thereafter. (day 1 then when CD3 levels > 25 cells/mm3). Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care. Bortezomib will be given at a dose of 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Methylprednisolone will be administered prior to each bortezomib dose. On days 2 and 5, administer methylprednisolone 100 mg intravenous push (IVP). On days 9 and 12, administer methylprednisolone 50 mg intravenous push (IVP). If thymoglobulin is administered the same day as bortezomib, the order of administration is- methylprednisolone, then bortezomib, then thymoglobulin.	Drug: Bortezomib; Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.; Other Names: Velcade ; Drug: Acetaminophen; Patients will be premedicated with acetaminophen prior to dosing per institution standard of care.; Other Names: Tylenol ; Drug: Antihistamine; Patients will be premedicated with an antihistamine prior to dosing per institution standard of care.; Other Names: diphenhydramine ; Drug: Methylprednisolone; Methylprednisolone 250 mg with 1st dose of Thymoglobulin. Methylprednisolone 125 mg on treatment day 2 subsequent corticosteroids per institution standard of care; following treatment, corticosteroid therapy will resume at the pre-rejection dose.; Other Names: Medrol

Outcome Measures

Primary Outcome Measures

1. Number of Patients in Each Group With Any of the Following: Rejection Reversal or Recurrent Rejection [1 year]

   Rejection Reversal is a return of serum creatinine to within 115% of the baseline value, or histologic reversal occurring within 14 days of initiation of treatment. Recurrent Rejection is histologic evidence of rejection noted on a biopsy specimen obtained up to 3 months after documented rejection reversal.

Secondary Outcome Measures

1. Number of Patients With Allografts With C4d Focal Positive Pretreatment Biopsy [Day 1]

2. Renal Allograft Survival [1 year after rejection treatment]

3. Mean Serum Creatinine [7, 14, 28, 60, 90 days and 1 year post therapy initiation]

   Renal allograft function as determined by change (∆) in Calculated creatinine clearance by Cockcroft-Gault at 7, 14, 28, 60, and 90 days and 1 year post therapy initiation

4. Incidence of Death [90 days]

5. Number of Patients With Allografts With C4d Diffuse Positive Pretreatment Biopsy [90 days]

6. Incidence of Post Transplant Lymphoproliferative Disorder (PTLD) [1 year]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

Each subject must meet all of the following inclusion criteria to be enrolled in the study:

• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.

• Female subject is either post-menopausal or surgically sterilized or willing to use two acceptable methods of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.

• Male subject agrees to use an acceptable method for contraception for the duration of the study.

• Subject is between 18 and 65 years of age, inclusive.

• Subject has a transplant dysfunction indicated by an increase in creatinine of 0.3 mg/dL or 15% (lipase >3 X ULN for kidney/pancreas recipients) over baseline necessitating an allograft biopsy to assess for allograft rejection.

• Presence of light microscopic histologic changes consistent with acute cellular rejection of a Banff 97 (2005 update) grade IA or greater and at least one of the following:

• Donor-specific antibody (DSA) positive via Luminex

• Presence of C4d in the peritubular capillaries or glomeruli

• Subject must have no known contraindications to treatment with bortezomib, boron or mannitol, thymoglobulin, or rituximab.

• Recipients of kidney or simultaneous kidney pancreas organ transplant.

Exclusion Criteria

Subjects meeting any of the following exclusion criteria are not to be enrolled in the study.

• Subject has a platelet count < 100,000/mm3 within 7 days before enrollment.

• Subject has an absolute neutrophil count of < 1,000/mm3 within 7 days before enrollment.

• Subject has Grade 2 peripheral neuropathy within 14 days before enrollment.

• Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (see section 8.4), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.

• Subject has received other investigational drugs with 14 days before enrollment

• Serious medical (other than renal disease) or psychiatric illness likely to interfere with participation in this clinical study.

• Subjects that have previously received an organ transplant other than kidney or simultaneous kidney pancreas.

• Subjects who are recipients of A-B-O incompatible transplants, all cytotoxicity (CDC) crossmatch positive transplants

• Recipients of a simultaneous kidney pancreas transplant that only have pancreas rejection.

• Subjects unable to tolerate a dose of mycophenolate mofetil 1-3g/day (or equivalent mycophenolic acid dose).

• Subjects who are anti-HIV-positive, or HBsAg-positive. Anti-Hepatitis C Virus (HCV) positive patients are excluded, except patients with negative pathologic complete remission-result.

• Recipients of a kidney from a donor who tests positive for HIV, HBsAg or anti-HCV

• History of malignancy within the past 5 years that is not considered to be cured, with the exception of localized basal cell carcinoma of the skin (excised ≥ 2 years prior to randomization)

• Subjects with current or recent severe systemic infections within the 2 weeks prior to randomization.

• Receipt of a live vaccine within 4 weeks prior to study entry

• Evidence of severe liver disease with abnormal liver profile (aspartate aminotransferase (AST), alanine aminotransferase (ALT) or total bilirubin > 3 times upper limit of normal (ULN)) at screening.

• Pregnant or nursing (lactating) women.

• EBV sero-mismatch (EBV + donor organ transplanted to EBV - recipient)

• CMV sero-mismatch (CMV + donor organ transplanted to CMV - recipient)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Christ Hospital	Cincinnati	Ohio	United States	45202
2	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45267

Sponsors and Collaborators

• University of Cincinnati

Investigators

• Principal Investigator: E. Steve Woodle, MD, University of Cincinnati

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: E. Steve Woodle, MD, FACS, University of Cincinnati
• ClinicalTrials.gov Identifier: NCT00771875
• Other Study ID Numbers: X05273
• First Posted: Oct 15, 2008
• Last Update Posted: Jan 27, 2016
• Last Verified: Dec 1, 2015

• Additional relevant MeSH terms: Acetaminophen; Diphenhydramine; Methylprednisolone; Rituximab; Bortezomib; Thymoglobulin; Antilymphocyte Serum; Histamine H1 Antagonists; Histamine Antagonists

Study Results

Participant Flow

Arm/Group Title	Rabbit Antithymocyte Globulin (RATG)	RATG/Rituximab	RATG/Bortezomib
Arm/Group Description	RATG Rabbit Antithymocyte Globulin (RATG): All patients will receive Thymoglobulin dosed based on cluster of differentiation 3 (CD3) count. Patients will be redosed when the CD3 count is ≥ 25. Depending on rejection severity, Thymoglobulin will be given for a maximum of 7-14 days. CD3 levels will be monitored daily. Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care. Bortezomib: Patient will receive 1.3 mg/m2 via intravenous push (IVP) over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.	Rabbit Antithymocyte Globulin (RATG) + Rituximab Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care.	Rabbit Antithymocyte Globulin (RATG) + Bortezomib Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.
Period Title: Overall Study
STARTED	10	10	10
COMPLETED	10	9	10
NOT COMPLETED	0	1	0

Baseline Characteristics

Arm/Group Title	Rabbit Antithymocyte Globulin (RATG)	RATG/Rituximab	RATG/Bortezomib	Total
Arm/Group Description	RATG Rabbit Antithymocyte Globulin (RATG): All patients will receive Thymoglobulin dosed based on CD3 count. Patients will be redosed when the CD3 count is ≥ 25. Depending on rejection severity, Thymoglobulin will be given for a maximum of 7-14 days. CD3 levels will be monitored daily. Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care. Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.	Rabbit Antithymocyte Globulin (RATG) + Rituximab Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care.	Rabbit Antithymocyte Globulin (RATG) + Bortezomib Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.	Total of all reporting groups
Overall Participants	10	9	10	29
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.9 (12.6)	34.2 (6.6)	38.5 (12.3)	35.8 (10.8)
Sex: Female, Male (Count of Participants)
Female	2 20%	4 44.4%	4 40%	10 34.5%
Male	8 80%	5 55.6%	6 60%	19 65.5%
Region of Enrollment (participants) [Number]
United States	10 100%	9 100%	10 100%	29 100%
Type of Transplant (participants) [Number]
Deceased Donor Kidney Transplant	2 20%	1 11.1%	3 30%	6 20.7%
Deceased Donor Simultaneous Pancreas/Kidney	1 10%	1 11.1%	2 20%	4 13.8%
Living Donor	7 70%	7 77.8%	5 50%	19 65.5%

Outcome Measures

1. Primary Outcome

Title	Number of Patients in Each Group With Any of the Following: Rejection Reversal or Recurrent Rejection
Description	Rejection Reversal is a return of serum creatinine to within 115% of the baseline value, or histologic reversal occurring within 14 days of initiation of treatment. Recurrent Rejection is histologic evidence of rejection noted on a biopsy specimen obtained up to 3 months after documented rejection reversal.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rabbit Antithymocyte Globulin (RATG)	RATG/Rituximab	RATG/Bortezomib
Arm/Group Description	RATG Rabbit Antithymocyte Globulin (RATG): All patients will receive Thymoglobulin dosed based on CD3 count. Patients will be redosed when the CD3 count is ≥ 25. Depending on rejection severity, Thymoglobulin will be given for a maximum of 7-14 days. CD3 levels will be monitored daily. Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care. Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.	Rabbit Antithymocyte Globulin (RATG) + Rituximab Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care.	Rabbit Antithymocyte Globulin (RATG) + Bortezomib Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.
Measure Participants	10	9	10
Rejection Recurrence	0 0%	0 0%	0 0%
Rejection Reversal	2 20%	1 11.1%	1 10%

2. Secondary Outcome

Title	Number of Patients With Allografts With C4d Focal Positive Pretreatment Biopsy
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rabbit Antithymocyte Globulin (RATG)	RATG/Rituximab	RATG/Bortezomib
Arm/Group Description	RATG Rabbit Antithymocyte Globulin (RATG): All patients will receive Thymoglobulin dosed based on CD3 count. Patients will be redosed when the CD3 count is ≥ 25. Depending on rejection severity, Thymoglobulin will be given for a maximum of 7-14 days. CD3 levels will be monitored daily. Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care. Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.	Rabbit Antithymocyte Globulin (RATG) + Rituximab Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care.	Rabbit Antithymocyte Globulin (RATG) + Bortezomib Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.
Measure Participants	10	9	10
Number [participants]	2 20%	2 22.2%	4 40%

3. Secondary Outcome

Title	Renal Allograft Survival
Time Frame	1 year after rejection treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rabbit Antithymocyte Globulin (RATG)	RATG/Rituximab	RATG/Bortezomib
Arm/Group Description	RATG Rabbit Antithymocyte Globulin (RATG): All patients will receive Thymoglobulin dosed based on CD3 count. Patients will be redosed when the CD3 count is ≥ 25. Depending on rejection severity, Thymoglobulin will be given for a maximum of 7-14 days. CD3 levels will be monitored daily. Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care. Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.	Rabbit Antithymocyte Globulin (RATG) + Rituximab Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care.	Rabbit Antithymocyte Globulin (RATG) + Bortezomib Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.
Measure Participants	10	9	10
Number [participants]	7 70%	7 77.8%	10 100%

4. Secondary Outcome

Title	Mean Serum Creatinine
Description	Renal allograft function as determined by change (∆) in Calculated creatinine clearance by Cockcroft-Gault at 7, 14, 28, 60, and 90 days and 1 year post therapy initiation
Time Frame	7, 14, 28, 60, 90 days and 1 year post therapy initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rabbit Antithymocyte Globulin (RATG)	RATG/Rituximab	RATG/Bortezomib
Arm/Group Description	RATG Rabbit Antithymocyte Globulin (RATG): All patients will receive Thymoglobulin dosed based on CD3 count. Patients will be redosed when the CD3 count is ≥ 25. Depending on rejection severity, Thymoglobulin will be given for a maximum of 7-14 days. CD3 levels will be monitored daily. Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care. Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.	Rabbit Antithymocyte Globulin (RATG) + Rituximab Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care.	Rabbit Antithymocyte Globulin (RATG) + Bortezomib Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.
Measure Participants	10	9	10
7 days	3.04 (1.67)	2.32 (0.89)	2.31 (0.78)
14 days	3.25 (1.76)	2.35 (0.95)	2.20 (0.69)
28 days	2.9 (1.23)	2.35 (0.90)	2.18 (0.47)
60 days	2.62 (1.23)	2.32 (0.87)	2.38 (0.62)
90 days	2.48 (1.18)	2.12 (1.01)	2.13 (0.54)
1 year	2.19 (0.84)	2.07 (1.10)	2.87 (1.37)

5. Secondary Outcome

Title	Incidence of Death
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rabbit Antithymocyte Globulin (RATG)	RATG/Rituximab	RATG/Bortezomib
Arm/Group Description	RATG Rabbit Antithymocyte Globulin (RATG): All patients will receive Thymoglobulin dosed based on CD3 count. Patients will be redosed when the CD3 count is ≥ 25. Depending on rejection severity, Thymoglobulin will be given for a maximum of 7-14 days. CD3 levels will be monitored daily. Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care. Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.	Rabbit Antithymocyte Globulin (RATG) + Rituximab Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care.	Rabbit Antithymocyte Globulin (RATG) + Bortezomib Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.
Measure Participants	10	9	10
Number [participants]	0 0%	0 0%	0 0%

6. Secondary Outcome

Title	Number of Patients With Allografts With C4d Diffuse Positive Pretreatment Biopsy
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rabbit Antithymocyte Globulin (RATG)	RATG/Rituximab	RATG/Bortezomib
Arm/Group Description	RATG Rabbit Antithymocyte Globulin (RATG): All patients will receive Thymoglobulin dosed based on CD3 count. Patients will be redosed when the CD3 count is ≥ 25. Depending on rejection severity, Thymoglobulin will be given for a maximum of 7-14 days. CD3 levels will be monitored daily. Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care. Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.	Rabbit Antithymocyte Globulin (RATG) + Rituximab Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care.	Rabbit Antithymocyte Globulin (RATG) + Bortezomib Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.
Measure Participants	10	9	10
Number [participants]	3 30%	3 33.3%	5 50%

7. Secondary Outcome

Title	Incidence of Post Transplant Lymphoproliferative Disorder (PTLD)
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rabbit Antithymocyte Globulin (RATG)	RATG/Rituximab	RATG/Bortezomib
Arm/Group Description	RATG Rabbit Antithymocyte Globulin (RATG): All patients will receive Thymoglobulin dosed based on CD3 count. Patients will be redosed when the CD3 count is ≥ 25. Depending on rejection severity, Thymoglobulin will be given for a maximum of 7-14 days. CD3 levels will be monitored daily. Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care. Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.	Rabbit Antithymocyte Globulin (RATG) + Rituximab Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care.	Rabbit Antithymocyte Globulin (RATG) + Bortezomib Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.
Measure Participants	10	9	10
Number [participants]	0 0%	0 0%	0 0%

Adverse Events

Time Frame	1 year
Arm/Group Title	Rabbit Antithymocyte Globulin (RATG)		RATG/Rituximab		RATG/Bortezomib
Arm/Group Description	RATG Rabbit Antithymocyte Globulin (RATG): All patients will receive Thymoglobulin dosed based on CD3 count. Patients will be redosed when the CD3 count is ≥ 25. Depending on rejection severity, Thymoglobulin will be given for a maximum of 7-14 days. CD3 levels will be monitored daily. Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care. Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.		Rabbit Antithymocyte Globulin (RATG) + Rituximab Rituximab: Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care.		Rabbit Antithymocyte Globulin (RATG) + Bortezomib Bortezomib: Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.
All Cause Mortality
	Rabbit Antithymocyte Globulin (RATG)		RATG/Rituximab		RATG/Bortezomib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Rabbit Antithymocyte Globulin (RATG)		RATG/Rituximab		RATG/Bortezomib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/10 (70%)		5/9 (55.6%)		7/10 (70%)
Blood and lymphatic system disorders
Serum Sickness	1/10 (10%)	1	0/9 (0%)	0	0/10 (0%)	0
Cardiac disorders
Coronary Artery Disease	2/10 (20%)	2	0/9 (0%)	0	0/10 (0%)	0
Gastrointestinal disorders
Gastrointestinal Disorder	3/10 (30%)	3	3/9 (33.3%)	3	2/10 (20%)	2
Dehydration	0/10 (0%)	0	0/9 (0%)	0	1/10 (10%)	1
Hemorrhage of Lower GI	0/10 (0%)	0	1/9 (11.1%)	1	0/10 (0%)	0
General disorders
Pain and Tenderness at Pheresis Line	0/10 (0%)	0	0/9 (0%)	0	1/10 (10%)	1
Infections and infestations
Infection	4/10 (40%)	4	4/9 (44.4%)	4	5/10 (50%)	5
Metabolism and nutrition disorders
Death due to hypoglycemic attack and respiratory distress	0/10 (0%)	0	1/9 (11.1%)	1	0/10 (0%)	0
Hyperkalemia	0/10 (0%)	0	1/9 (11.1%)	1	0/10 (0%)	0
Hyperglycemia	0/10 (0%)	0	2/9 (22.2%)	2	0/10 (0%)	0
Nervous system disorders
Dizziness	1/10 (10%)	1	0/9 (0%)	0	0/10 (0%)	0
Renal and urinary disorders
Renal Dysfunction	7/10 (70%)	19	5/9 (55.6%)	10	7/10 (70%)	20
Surgical and medical procedures
Surgical Complication	4/10 (40%)	4	1/9 (11.1%)	1	0/10 (0%)	0
Vascular disorders
Thombosis	0/10 (0%)	0	1/9 (11.1%)	1	2/10 (20%)	2
Other (Not Including Serious) Adverse Events
	Rabbit Antithymocyte Globulin (RATG)		RATG/Rituximab		RATG/Bortezomib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/10 (100%)		9/9 (100%)		7/10 (70%)
Blood and lymphatic system disorders
Grade 2 Anemia	5/10 (50%)	5	2/9 (22.2%)	2	3/10 (30%)	3
Grade 3 Anemia	5/10 (50%)	5	4/9 (44.4%)	5	2/10 (20%)	2
Grade 4 Anemia	1/10 (10%)	1	2/9 (22.2%)	2	0/10 (0%)	0
Gastrointestinal disorders
Grade 1 Nausea/Vomiting	6/10 (60%)	6	2/9 (22.2%)	2	5/10 (50%)	5
Grade 2 Nausea/Vomiting	1/10 (10%)	1	5/9 (55.6%)	5	2/10 (20%)	2
Grade 1 Diarrhea	6/10 (60%)	6	3/9 (33.3%)	3	3/10 (30%)	3
General disorders
Productive Cough	0/10 (0%)	0	0/9 (0%)	0	1/10 (10%)	1
Infections and infestations
Urinary Tract Infection	0/10 (0%)	0	1/9 (11.1%)	1	0/10 (0%)	0
Cytomegalovirus (CMV) infection	0/10 (0%)	0	1/9 (11.1%)	1	0/10 (0%)	0
BK Virus	0/10 (0%)	0	1/9 (11.1%)	1	0/10 (0%)	0
Metabolism and nutrition disorders
Grade 4 Thrombocytopenia	0/10 (0%)	0	2/9 (22.2%)	2	0/10 (0%)	0
Renal and urinary disorders
Worsened Peripheral Neuropathy	1/10 (10%)	1	1/9 (11.1%)	1	2/10 (20%)	2
Level 1 Peripheral Neuropathy	5/10 (50%)	5	3/9 (33.3%)	4	4/10 (40%)	4
Level 2 Peripheral Neuropathy	0/10 (0%)	0	3/9 (33.3%)	3	4/10 (40%)	4
Level 3 Peripheral Neuropathy	0/10 (0%)	0	2/9 (22.2%)	2	2/10 (20%)	2
Grade 2 Peripheral Neuropathy	0/10 (0%)	0	0/9 (0%)	0	1/10 (10%)	1
Level 4 Peripheral Neuropathy	0/10 (0%)	0	0/9 (0%)	0	1/10 (10%)	1
Level 5 Peripheral Neuropathy	0/10 (0%)	0	0/9 (0%)	0	1/10 (10%)	1
Skin and subcutaneous tissue disorders
Tingling	0/10 (0%)	0	0/9 (0%)	0	1/10 (10%)	1

Limitations/Caveats

[Not Specified]

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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.