Effects of Rituximab and Mycophenolate Mofetil on Anti-Donor Antibody Production in Patients Awaiting Transplant - Full Text View

Sponsors and Collaborators:	University of Washington Genentech
Information provided by:	University of Washington
ClinicalTrials.gov Identifier:	NCT00446251

Purpose

Increasingly patients who have been pre-sensitized to human tissue by prior transplants, blood transfusion or pregnancy are being added to the kidney transplant waiting list. Currently over 30% of the patients on the national waiting list have a panel reactive antibody (PRA) titer over 9%. On average, increasing the PRA from 0 to 50% specifically in the Washington Organ Procurement Organization (OPO) increases the waiting time from 3 to 6 years; spontaneous decreases in the PRA rarely occur. Thus the probability of transplantation in sensitized patients is significantly decreased.

This is a 12-month phase 2, prospective, open label study to evaluate the effect of rituximab added to mycophenolate mofetil on the PRA of 15 patients who have already completed an 8 month trial of mycophenolate mofetil (MMF) treatment alone to reduce their PRA's below 10%.

PRA values obtained over 8 months from initiating MMF and the following 8 months from initiating Rituximab will be compared to the subject's historic values prior to the study and population controls (patients on the transplant waiting list who did not participate in the study). At 12 months the efficacy of Rituximab added to MMF will be evaluated using descriptive analysis.

Condition	Intervention	Phase
Kidney Failure, Chronic Diabetic Nephropathies Glomerulonephritis, IGA Hypertension, Renal	Drug: Rituximab Drug: Mycophenolate mofetil (MMF)	Phase II

MedlinePlus related topics: Diabetic Kidney Problems High Blood Pressure Kidney Failure Kidney Transplantation

Drug Information available for: Rituximab Immunoglobulins Globulin, Immune Mycophenolate Mofetil Mycophenolate mofetil hydrochloride

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study
Official Title:	The Highly Sensitized Patients: Effects of Rituximab and Mycophenolate Mofetil on Anti-HLA Antibody Production in Patients Awaiting Cadaveric Renal Transplant

Further study details as provided by University of Washington:

Primary Outcome Measures:

Primary Efficacy Endpoint: Proportion of subjects who achieve a PRA value below 10% within 6 months of study initiation. [ Time Frame: Month 6 of starting study ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Secondary Efficacy Endpoints: Change from baseline in subject's PRA at 4, 6, and 8 months [ Time Frame: Month 8 of starting study ] [ Designated as safety issue: No ]
Proportion of subjects with a negative crossmatch [ Time Frame: Month 8 of starting study ] [ Designated as safety issue: No ]

Estimated Enrollment:	15
Study Start Date:	December 2006
Estimated Study Completion Date:	December 2008
Estimated Primary Completion Date:	September 2008 (Final data collection date for primary outcome measure)

Intervention Details:

Rituximab dose is 1,000 mg given as an IV infusion every two weeks for 2 doses (days 1 and 15).

Cellcept is continued from prior study, taken 500mg BID, PO.

Show Detailed Description

Eligibility

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Age range 18 - 75, inclusive
Able and willing to give written informed consent and comply with the requirements of the study protocol
Outpatient status
Patients with a PRA over 10% after an 8-month trial of MMF monotherapy
Patients with updated immunizations for tetanus, influenza, hepatitis B, pneumococcus
Patients with a negative PPD (purified protein derivative) test within the last 6 months. If subject has a prior history of TB (tuberculosis) or positive PPD, documentation of adequate treatment is required.
Women who are of childbearing potential must have a negative serum pregnancy test prior to being enrolled in the study and agree to use a medically acceptable method of contraception throughout the study and for twelve months (1 year) after completion of treatment.
Men must agree to use an acceptable method of birth control during treatment and for twelve months (1 year) after completion of treatment.
ALT/AST less than 2 times the normal limit.

Exclusion Criteria:

Active infection
Receipt of live vaccine within 4 weeks prior to first infusion.
Previous treatment with rituximab (MabThera® / Rituxan®)
History of multiple recurrent infections defined as more than 3 urinary tract infections, 2 episodes of pneumonia or 3 episodes of otitis/sinusitis in one year, or more than two dialysis line or peritoneal infections within one year.
Infection with HCV (hepatitis C virus) or HBV (hepatitis B virus) or HIV (human immunodeficiency virus), lack of documentation of treatment of a positive PPD, pregnant or breast-feeding, baseline leukopenia, WBC less than 4.0, thrombocytopenia (platelet count less than 100,000/mm) or difficult to treat anemia, HCT chronically less than 32 on intravenous iron and EPO (erythropoietin) therapy, history of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies.
Concomitant malignancies or previous malignancies within the last five years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
History of psychiatric disorder
Significant cardiac or pulmonary disease (including obstructive pulmonary disease)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00446251

Sponsors and Collaborators

University of Washington

Genentech

Investigators

Principal Investigator:

Connie L Davis, MD

University of Washington

More Information

Publications:

Aranda JM Jr, Scornik JC, Normann SJ, Lottenberg R, Schofield RS, Pauly DF, Miles M, Hill JA, Sleasman JW, Skoda-Smith S. Anti-CD20 monoclonal antibody (rituximab) therapy for acute cardiac humoral rejection: a case report. Transplantation. 2002 Mar 27;73(6):907-10.

Dafoe DC, Bromberg JS, Grossman RA, Tomaszewski JE, Zmijewski CM, Perloff LJ, Naji A, Asplund MW, Alfrey EJ, Sack M, et al. Renal transplantation despite a positive antiglobulin crossmatch with and without prophylactic OKT3. Transplantation. 1991 Apr;51(4):762-8.

Garrett HE Jr, Groshart K, Duvall-Seaman D, Combs D, Suggs R. Treatment of humoral rejection with rituximab. Ann Thorac Surg. 2002 Oct;74(4):1240-2.

Gloor JM, Lager DJ, Moore SB, Pineda AA, Fidler ME, Larson TS, Grande JP, Schwab TR, Griffin MD, Prieto M, Nyberg SL, Velosa JA, Textor SC, Platt JL, Stegall MD. ABO-incompatible kidney transplantation using both A2 and non-A2 living donors. Transplantation. 2003 Apr 15;75(7):971-7.

Hack N, Angra S, Friedman E, McKnight T, Cardella CJ. Anti-idiotypic antibodies from highly sensitized patients stimulate B cells to produce anti-HLA antibodies. Transplantation. 2002 Jun 27;73(12):1853-8.

Holechek MJ, Hiller JM, Paredes M, Rickard JC, Montgomery RA. Expanding the living organ donor pool: positive crossmatch and ABO incompatible renal transplantation. Nephrol Nurs J. 2003 Apr;30(2):195-204.

Jillella AP, Dainer PM, Kallab AM, Ustun C. Treatment of a patient with end-stage renal disease with Rituximab: pharmacokinetic evaluation suggests Rituximab is not eliminated by hemodialysis. Am J Hematol. 2002 Nov;71(3):219-22.

Libetta C, Rampino T, Dal Canton A. Polarization of T-helper lymphocytes toward the Th2 phenotype in uremic patients. Am J Kidney Dis. 2001 Aug;38(2):286-95.

Maloney DG, Grillo-Lopez AJ, Bodkin DJ, White CA, Liles TM, Royston I, Varns C, Rosenberg J, Levy R. IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol. 1997 Oct;15(10):3266-74.

Miura S, Okazaki H, Satoh T, Amada N, Ohashi Y. Long-term follow-up of living donor renal transplant recipients sensitized after donor specific blood transfusion. Transplant Proc. 2001 Feb-Mar;33(1-2):1221-3. No abstract available.

Nitta K, Akiba T, Kawashima A, Kimata N, Miwa N, Nishida E, Uchida K, Honda K, Yumura W, Nihei H. Characterization of TH1/TH2 profile in uremic patients. Nephron. 2002 Jul;91(3):492-5.

Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, Newman RA, Hanna N, Anderson DR. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994 Jan 15;83(2):435-45.

Schweitzer EJ, Wilson JS, Fernandez-Vina M, Fox M, Gutierrez M, Wiland A, Hunter J, Farney A, Philosophe B, Colonna J, Jarrell BE, Bartlett ST. A high panel-reactive antibody rescue protocol for cross-match-positive live donor kidney transplants. Transplantation. 2000 Nov 27;70(10):1531-6.

Takeda A, Uchida K, Haba T, Tominaga Y, Katayama A, Kobayashi T, Oikawa T, Morozumi K. Acute humoral rejection of kidney allografts in patients with a positive flow cytometry crossmatch (FCXM). Clin Transplant. 2000;14 Suppl 3:15-20.

Yokoyama T, Nitta K, Futatsuyama K, Hayashi T, Honda K, Uchida K, Kawashima A, Yumura W, Nihei H. Identification of T helper cell subsets in continuous ambulatory peritoneal dialysis patients. Nephron. 2001 Oct;89(2):215-8.

Vieira CA, Agarwal A, Book BK, Sidner RA, Zeni T, Gebel HM, Roggero AL, Fineberg NA, Taber T, Kraus MA, Pescovitz MD. Rituxan for reduction of anti-HLA antibodies in patients awaiting renal transplantation. Am J Transplantation 2002;2:A870.

Responsible Party:	University of Washington ( Dr. Connie Davis )
Study ID Numbers:	04-0927-A 05
Study First Received:	March 9, 2007
Last Updated:	August 18, 2008
ClinicalTrials.gov Identifier:	NCT00446251
Health Authority:	United States: Food and Drug Administration

Keywords provided by University of Washington:

Dialysis
Kidney
Renal
Nephropathy
Glomerulonephropathy
Immunosuppression

Graft
Compatibility
Transplant
Diabetes
Hypertension
Transplantation, Kidney

Study placed in the following topic categories:

Glomerulonephritis
Renal Insufficiency
Diabetic Nephropathies
Kidney Failure, Chronic
Mycophenolic Acid
Hypertension, Renal
Urologic Diseases
Renal hypertension
Berger disease
Mycophenolate mofetil
Kidney Diseases
Diabetes Complications
Immunoglobulins

Autoimmune Diseases
Rituximab
Diabetes Mellitus
Vascular Diseases
Endocrine System Diseases
Antibodies
Renal Insufficiency, Chronic
Nephritis
Glomerulonephritis, IGA
Endocrinopathy
Hypertension
Kidney Failure

Additional relevant MeSH terms:

Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Immune System Diseases
Antineoplastic Agents
Therapeutic Uses
Physiological Effects of Drugs

Enzyme Inhibitors
Cardiovascular Diseases
Antirheumatic Agents
Antibiotics, Antineoplastic
Immunosuppressive Agents
Pharmacologic Actions

ClinicalTrials.gov processed this record on January 16, 2009