Randomized Trial for Mixed Acute Rejection

NCT ID: NCT00771875

Last Updated: 2016-01-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-09-30
• Study Completion Date: 2013-03-31

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.

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.

Conditions

Graft Rejection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Rabbit Antithymocyte Globulin (RATG)

Intervention Type: DRUG

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

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Acetaminophen

Intervention Type: DRUG

Patients will be premedicated with acetaminophen prior to dosing per institution standard of care.

Antihistamine

Intervention Type: DRUG

Patients will be premedicated with an antihistamine prior to dosing per institution standard of care.

Methylprednisolone

Intervention Type: DRUG

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.

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.

Group Type: EXPERIMENTAL

Rituximab

Intervention Type: DRUG

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.

Acetaminophen

Intervention Type: DRUG

Patients will be premedicated with acetaminophen prior to dosing per institution standard of care.

Antihistamine

Intervention Type: DRUG

Patients will be premedicated with an antihistamine prior to dosing per institution standard of care.

Methylprednisolone

Intervention Type: DRUG

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.

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.

Group Type: EXPERIMENTAL

Bortezomib

Intervention Type: DRUG

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.

Acetaminophen

Intervention Type: DRUG

Patients will be premedicated with acetaminophen prior to dosing per institution standard of care.

Antihistamine

Intervention Type: DRUG

Patients will be premedicated with an antihistamine prior to dosing per institution standard of care.

Methylprednisolone

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Acetaminophen

Patients will be premedicated with acetaminophen prior to dosing per institution standard of care.

Intervention Type: DRUG

Antihistamine

Patients will be premedicated with an antihistamine prior to dosing per institution standard of care.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

thymoglobulin; rituxan; Velcade; Tylenol; diphenhydramine; Medrol

Eligibility Criteria

Inclusion Criteria

• 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

• 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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Cincinnati

OTHER

Sponsor Role: lead

Responsible Party

E. Steve Woodle

MD, FACS

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

E. Steve Woodle, MD

Role: PRINCIPAL_INVESTIGATOR

University of Cincinnati

Locations

The Christ Hospital

Cincinnati, Ohio, United States

University of Cincinnati Medical Center

Cincinnati, Ohio, United States

Countries

United States

Other Identifiers

X05273

Identifier Type: -

Identifier Source: org_study_id