Rituximab in Renal Allograft Recipients Who Develop Early De Novo Anti-HLA Alloantibodies

NCT00307125 | Completed Phase 2 Results DMC

• 2 other identifiers: DAIT CTOT-02CCTPT-02
• Study Type: interventional
• Target: 757
• Locations: 1 country
• Sites: 17

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.

Conditions

Kidney Transplant; Kidney Transplant Recipient; Graft Function/Survival; de Novo HLA Antibodies Development

Keywords

Organ Transplantation; Graft function/survival; Immunosuppression; anti-CD20 (rituximab)

Outcome Measures

Primary Outcomes (3)

• During Screening Phase: Incidence of Alloantibody Development

  Data were analyzed for 653 participants from the screening phase of the study. This outcome looked at the number of kidney transplant recipients that developed de novo HLA antibodies (anti-HLA Ab) post-transplant. Alloantibody is defined as an antibody produced following the introduction of an alloantigen into the system of an individual lacking that particular antigen. Alloantibodies are important mediators of acute and chronic rejection.

  During screening window of 3-60 months post kidney transplant

• During Screening Phase: Timing of Alloantibody Development

  Data were analyzed for 653 participants from the screening phase of the study. Of these, 79 (12%) developed de novo HLA-antibodies (anti-HLA Ab). This outcome looks at the average length of time (interval) from post kidney transplant until development of alloantibody. Alloantibody is defined as an antibody produced following the introduction of an alloantigen into the system of an individual lacking that particular antigen. Alloantibodies are important mediators of acute and chronic rejection

  During screening window of 3-60 months post kidney transplant

• Number of Participants With 50 Percent (%) Decrease in Circulating Anti-Human Leukocyte Antigen (HLA) Antibodies

  Number of participants with 50% decrease in circulating anti-HLA antibodies at any time within the first 12 months post kidney transplant by LuminexTM Beads Method. Luminex assays for quantitation and detection of cytokine and signal transduction proteins. Presence of circulating antibodies is indicative of the transplant recipient's immune system responding to the transplanted organ as a foreign object or infection.

  1 year post treatment initiation

Secondary Outcomes (7)

• Number of Deaths 12 Months Post Treatment Initiation

  12 months post treatment initiation

• Number of Participants Experiencing Graft Loss 12 Months Post Treatment Initiation

  1 year post treatment initiation

• Number of Participants Experiencing Biopsy-proven Post-Transplant Lymphoproliferative Disease (PTLD)

  1 year post treatment initiation

• Number of Participants Experiencing Loss of Peritubular Capillary (PTC) C4d Staining on Kidney Biopsy

  1 year post treatment initiation

• Number of Participants With Viral Replication of Cytomegalovirus (CMV)

  1 year post treatment initiation

Study Arms (2)

Pilot Phase-Rituximab plus immunosuppression

EXPERIMENTAL

Enrollment into a Stage 2 pilot treatment study will occur after Stage 1. Adult Rituximab Dosing (Subjects \> 18 years): 1000 mg on days 0 and 14; Pediatric Rituximab Dosing (Subjects \<\\=18 years): 375 mg/m\^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22). Standard immunosuppression is site-specific.

Drug: Rituximab plus immunosuppression

Pilot Phase-Placebo plus immunosuppression

PLACEBO COMPARATOR

Adult Placebo Dosing (Subjects \>18 years): 1000 mg on days 0 and 14; Pediatric Placebo Dosing (Subject \<\\=18 years): 375 mg/m\^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22). Standard immunosuppression is site-specific.

Drug: Placebo plus immunosuppression

Interventions

Rituximab plus immunosuppression DRUG

Genetically engineered monoclonal antibody directed against the CD20 antigen on B cells and is known to deplete B cells when administered intravenously. Generally used in the treatment of non-Hodgkin's lymphoma Standard immunosuppression is site-specific.

Also known as: Rituxan®, MabThera®, anti-CD20

Pilot Phase-Rituximab plus immunosuppression

Placebo plus immunosuppression DRUG

Placebo dosing: Adult Dosing (Subjects \>18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subject \<\\=18 years): 375 mg/m\^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22). Standard immunosuppression is site-specific.

Also known as: Placebo for rituximab

Pilot Phase-Placebo plus immunosuppression

Eligibility Criteria

• Age: 5 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Clinical Trials in Organ Transplantation: collaborator
• Cooperative Clinical Trials in Pediatric Transplantation (CCTPT): collaborator

Study Sites (17)

University of Alabama, Pediatric Nephrology

Birmingham, Alabama, 35294, United States

Location

University of Alabama

Birmingham, Alabama, 35294, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

University of Florida

Gainesville, Florida, 32601, United States

Location

University of Illinois

Chicago, Illinois, 60607, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

University of Maryland

Baltimore, Maryland, 21201, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Children's Hospital Boston

Boston, Massachusetts, 02115, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Saint Barnabas Medical Center

Livingston, New Jersey, 07039, United States

Location

Legacy Transplant Services

Portland, Oregon, 97210, United States

Location

Oregon Health Science University

Portland, Oregon, 97219, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

The Methodist Hospital

Houston, Texas, 77030, United States

Location

Children's Hospital and Regional Medical Center

Seattle, Washington, 98105, United States

Location

Related Publications (4)

• 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.

  PMID: 12438971 BACKGROUND

• 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.

  PMID: 12394606 BACKGROUND

• 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.

  PMID: 12698094 BACKGROUND

• 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.

  PMID: 28346714 DERIVED

Related Links

• Click here for the Clinical Trials in Organ Transplantation (CTOT) public Web site

MeSH Terms

Interventions

Rituximab; Immunosuppression Therapy

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immunotherapy; Immunomodulation; Biological Therapy; Therapeutics; Immunologic Techniques; Investigative Techniques

Limitations and Caveats

Slow accrual. In order to ensure the study was completed within the time frame allotted, randomization to the control arm (Pilot Phase-Placebo plus immunosuppression) was suspended. Enrollment continued to lag. The study was stopped early.

Results Point of Contact

• Title: Director, Clinical Research Operations Program (CROP)
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• Mohamed H. Sayegh, MD

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

• William Harmon, MD

  Boston Children's Hospital

  PRINCIPAL INVESTIGATOR

• Anil Chandraker, MD

  Brigham and Women's Hospital

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 23, 2006
• First Posted: March 27, 2006
• Study Start: March 1, 2006
• Primary Completion: December 1, 2012
• Study Completion: December 1, 2012
• Last Updated: March 23, 2015
• Results First Posted: March 23, 2015

Record last verified: 2015-03

Locations

US (17)