Clinical trial NCT00307125: Rituximab in Renal Allograft Recipients Who Develop Early De Novo Anti-HLA Alloantibodies
Official title: B-Cell Depletion by Anti-CD20 (Rituximab) in Renal Allograft Recipients Who Develop Early De Novo Anti-HLA Alloantibodies Will Result in Inhibition of Alloantibody Production and Attenuation of Chronic Humoral Rejection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Kidney Transplant
Kidney Transplant Recipient
Graft Function/Survival
de Novo HLA Antibodies Development
Keywords: Organ Transplantation
Graft function/survival
Immunosuppression
anti-CD20 (rituximab)
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Clinical Trials in Organ Transplantation
name: Cooperative Clinical Trials in Pediatric Transplantation (CCTPT)
First posted: 2006-03-27
Enrollment: 757
Sex: ALL
Minimum age (years): 5
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether treatment with rituximab (anti-CD20, Rituxan®, MabThera®) in individuals who develop new anti-HLA antibodies after renal (kidney) transplant will promote longer-term survival of the transplanted kidney.The pilot study compares the use of rituximab (Rituxan®) + site-specific standard immunosuppression to placebo + site-specific standard immunosuppression in the treatment of circulating anti-HLA antibodies in subjects who develop de novo anti-HLA antibodies between 3-36 months after transplant.

Detailed description: Organ rejection occurs when a patient's body does not recognize the new organ and attacks it. Data suggest that the development of anti-human leukocyte antigen (HLA) antibodies is an early clinical indication that organ rejection may occur. Rituximab is a genetically engineered monoclonal antibody directed against the CD20 antigen on B cells and is known to deplete B cells when administered intravenously; it is FDA-approved for the treatment of non-Hodgkin's lymphoma; Chronic Lymphocytic Leukemia (CLL); and Rheumatoid Arthritis (RA) in combination with methotrexate in adult patients with moderately-to severely-active RA who have inadequate response to one or more TNF antagonist therapies.

In a previous small study, kidney transplant patients with either acute humoral rejection (AHR) or chronic humoral rejection (CHR) were given rituximab and other antilymphocyte therapy. Patients with AHR had lower or undetectable levels of circulating anti-HLA antibodies after study treatment, and patients with CHR had a sustained decrease of anti-HLA antibodies to undetectable after 6 to 9 months.

This study will evaluate the safety and efficacy of rituximab in 1.)preventing organ rejection and 2.)promoting long-term survival of donor kidneys in people who undergo kidney transplantation.

This study involves two stages:

1. Stage 1 begins 3 to 36 months after transplant. During Stage 1, blood collection will occur every 3 months for up to 36 months after transplant to test for anti-HLA antibodies. When these antibodies are detected twice within 1 month, the patient will undergo a baseline kidney biopsy and have his or her glomerular filtration rate (GFR) measured to determine kidney function. If a patient meets certain study criteria, he or she will enter Stage 2 (Pilot Treatment Study).

   If anti-HLA antibodies are not detected in a patient's blood during Stage 1, the patient's participation will be complete.
2. In Stage 2, patients will receive site-specific standard immunosuppression plus randomization to either rituximab or placebo:

   * Adult dosing (\>18 years of age), will receive an intravenous infusion of 1000mg of rituximab on Days 0 and 14.
   * Pediatric dosing (\<\\= than 18 years of age) will receive an intravenous infusion of 375 mg/m\^2/dose (maximum 500 mg/dose) in 4 doses of rituximab on Days 0, 8, 15 and 22.

Adult participants will have 7-9 study visits over 12-24 months. Pediatric participants will have 9-11 study visits over 12-24 months. A physical exam, medication history, adverse events assessment, and blood and urine collection will occur at all visits. A biopsy of the kidney transplant will occur at Stage 2 entry and Month 12.

Note: Prior to January 2010, Stage 2 of this was a double-blind (double-masked) randomized pilot treatment study. As of January 2010 and beyond:

* subjects were no longer being recruited in the placebo treatment arm
* all treatment assignments were unblinded and an open-label design commenced; therefore, medication assignments were open to the study participants as well as to the site clinical team.
* all study subjects who participated in the study prior to this change were informed of the change
* all subjects who were randomized to the placebo-controlled arm and continued to meet the pilot study eligibility criteria were provided the option to participate in the pilot treatment study.

Eligibility criteria: Stage 1 Inclusion Criteria for All Participants:

* Willing to provide informed consent
* Previously diagnosed end stage renal disease (ESRD)
* Received kidney transplant within 3 and 36 months of study entry
* Willing to comply with the study protocol
* Willing to use acceptable forms of contraception during the study and for 12 months following rituximab/placebo therapy
* Willing to refrain from breastfeeding during the study and for 12 months following rituximab therapy

Stage 1 Inclusion Criteria for Pediatric Participants (\<\\=18 Years of Age):

* Parent or guardian willing to provide informed consent
* Have received all childhood vaccinations prior to study entry

Stage 2 Inclusion Criteria for Pilot Treatment Study:

* Three to 39 months post-transplant
* Developed new antibodies detected at two time points within 1 month between 3 to 36 months post-transplant
* Negative pregnancy test

Stage 1 Exclusion Criteria for All Participants:

* Recipient of a kidney from a donor older than 70 years of age
* Multi-organ transplant
* History of organ transplantation other than current kidney transplantation
* Previous treatment with rituximab
* History of severe allergic reactions to monoclonal antibodies
* History of allergic reaction to iodine glomerular filtration rate (GFR) assay
* Lack of intravenous (IV) access
* Sensitized to greater than 5% Panel Reactive Antibody (PRA) within 12 weeks prior to transplant
* History of recurrent bacterial or other significant infections
* Known active bacterial, viral, fungal, mycobacterial, or other infection (including tuberculosis \[TB\] or atypical mycobacterial disease) or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of study entry. Patients with fungal infections of nail beds are not excluded.
* HIV infected
* Surface antigen positive for hepatitis B virus (HBV)
* Antibody positive for hepatitis C virus (HCV)
* History of drug, alcohol, or chemical abuse within 6 months prior to study entry
* History of cancer. Patients with adequately treated in situ cervical carcinoma or adequately treated basal or squamous cell carcinoma of the skin are not excluded.
* Clinically significant cardiovascular or pulmonary disease
* Evidence of urinary tract obstruction causing decreased kidney function, unless corrected by study entry
* Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that would contraindicate use of an investigational drug, may affect interpretation of study results, or put the patient at high risk for treatment complications
* History of psychiatric disorder that may interfere with participation in the study
* History of nonadherence to prescribed regimens
* Use of other investigational drugs within 4 weeks of study entry
* Received any licensed or investigational live attenuated vaccine within 2 months of study entry.

Stage 2 Exclusion Criteria for All Participants:

* Previous treatment with rituximab
* Immunoglobulin Levels \<500mg/dL (Combined IgM, IgG, IgA, IgE, IgD)
* History of severe allergic reactions to monoclonal antibodies
* History of cancer. Patients with adequately treated in situ cervical carcinoma or adequately treated basal or squamous cell carcinoma of the skin are not excluded.
* Active systemic infection at the time of entry into Stage 2
* Recurrent or de novo glomerular disease or Banff Grade III chronic rejection other than chronic humoral rejection (CHR) indicated in baseline kidney biopsy post-transplant
* History of post-transplant lymphoproliferative disease (PTLD)
* Serum creatinine of 3.0 mg/dl or greater OR GFR less than 25 ml/min at the time of entry into Stage 2
* Hemoglobin less than 8.5 g/dl
* Platelets less than 80,000 cells/mm\^3
* White blood cell count less than 3,000 cells/mm\^3
* AST or ALT 2.5 times the upper limit of normal at study entry
* Pregnant or breast-feeding
* Absolute neutrophil count less than 1000/mm\^3

Stage 2 Exclusion Criteria for Pediatric Participants (\<\\=18 Years of Age):

* Positive test for parvovirus (B19) by PCR in the blood.

Primary outcomes:
measure: During Screening Phase: Incidence of Alloantibody Development
timeFrame: During screening window of 3-60 months post kidney transplant
measure: During Screening Phase: Timing of Alloantibody Development
timeFrame: During screening window of 3-60 months post kidney transplant
measure: Number of Participants With 50 Percent (%) Decrease in Circulating Anti-Human Leukocyte Antigen (HLA) Antibodies
timeFrame: 1 year post treatment initiation
Secondary outcomes:
measure: Number of Deaths 12 Months Post Treatment Initiation
timeFrame: 12 months post treatment initiation
measure: Number of Participants Experiencing Graft Loss 12 Months Post Treatment Initiation
timeFrame: 1 year post treatment initiation
measure: Number of Participants Experiencing Biopsy-proven Post-Transplant Lymphoproliferative Disease (PTLD)
timeFrame: 1 year post treatment initiation
measure: Number of Participants Experiencing Loss of Peritubular Capillary (PTC) C4d Staining on Kidney Biopsy
timeFrame: 1 year post treatment initiation
measure: Number of Participants With Viral Replication of Cytomegalovirus (CMV)
timeFrame: 1 year post treatment initiation
measure: Number of Participants With Evidence of Viral Replication of Epstein-Barr Virus (EBV)
timeFrame: 1 year post treatment initiation
measure: Number of Participants With Viral Replication of Polyomavirus (BKV)
timeFrame: 1 year post treatment initiation
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama, Pediatric Nephrology
state: Alabama
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Chicago
country: United States
facility: University of Illinois
state: Illinois
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Livingston
country: United States
facility: Saint Barnabas Medical Center
state: New Jersey
city: Portland
country: United States
facility: Legacy Transplant Services
state: Oregon
city: Portland
country: United States
facility: Oregon Health Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Houston
country: United States
facility: The Methodist Hospital
state: Texas
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center
state: Washington
Study officials:
affiliation: Brigham and Women's Hospital
name: Mohamed H. Sayegh, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Boston Children's Hospital
name: William Harmon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Brigham and Women's Hospital
name: Anil Chandraker, MD
role: STUDY_CHAIR
References:
citation: Lee PC, Terasaki PI, Takemoto SK, Lee PH, Hung CJ, Chen YL, Tsai A, Lei HY. All chronic rejection failures of kidney transplants were preceded by the development of HLA antibodies. Transplantation. 2002 Oct 27;74(8):1192-4. doi: 10.1097/00007890-200210270-00025.
citation: Mauiyyedi S, Colvin RB. Humoral rejection in kidney transplantation: new concepts in diagnosis and treatment. Curr Opin Nephrol Hypertens. 2002 Nov;11(6):609-18. doi: 10.1097/00041552-200211000-00007.
citation: Worthington JE, Martin S, Al-Husseini DM, Dyer PA, Johnson RW. Posttransplantation production of donor HLA-specific antibodies as a predictor of renal transplant outcome. Transplantation. 2003 Apr 15;75(7):1034-40. doi: 10.1097/01.TP.0000055833.65192.3B.
citation: Fishman JA, Ikle DN, Wilkinson RA. Discrepant serological assays for Pneumococcus in renal transplant recipients - a prospective study. Transpl Int. 2017 Jul;30(7):689-694. doi: 10.1111/tri.12959. Epub 2017 May 2.