Randomized Trial for Mixed Acute Rejection

Graft Rejection Clinical Trial

Official title:

B-Cell Targeted Therapy for Acute Renal Allograft Rejection With an Antibody Mediated Component: A Prospective, Randomized, Open-Label Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00771875
• Other study ID #: X05273
• Status: Completed
• Phase: Phase 2
• First received: October 14, 2008
• Last updated: December 17, 2015
• Start date: September 2008
• Est. completion date: March 2013

Study information

• Verified date: December 2015
• Source: University of Cincinnati
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: March 2013
• Est. primary completion date: December 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Graft Rejection

Intervention

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

Locations

Country	Name	City	State
United States	The Christ Hospital	Cincinnati	Ohio
United States	University of Cincinnati Medical Center	Cincinnati	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
University of Cincinnati

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Patients in Each Group With Any of the Following: Rejection Reversal or Recurrent Rejection	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.	1 year	No
Secondary	Number of Patients With Allografts With C4d Focal Positive Pretreatment Biopsy		Day 1	No
Secondary	Renal Allograft Survival		1 year after rejection treatment	No
Secondary	Mean Serum Creatinine	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	7, 14, 28, 60, 90 days and 1 year post therapy initiation	No
Secondary	Incidence of Death		90 days	Yes
Secondary	Number of Patients With Allografts With C4d Diffuse Positive Pretreatment Biopsy		90 days	No
Secondary	Incidence of Post Transplant Lymphoproliferative Disorder (PTLD)		1 year	No