Research Study of ATG and Rituximab in Renal Transplantation

Early Phase 1TerminatedNCT01318915

National Institute of Allergy and Infectious Diseases (NIAID)10 enrolled

Overview

The purpose of this study is see if a combination of two drugs, (ATG and rituximab), given at the time of the transplant surgery, will help reduce or eliminate the need for long term immunosuppressive medication.

Kidneys remove excess fluid and waste from the blood. When kidneys lose their filtering ability, dangerous levels of fluid and waste accumulate in the body - a condition known as kidney failure. There are two ways to treat kidney failure. One way is to get dialysis indefinitely. The second way is to get a kidney transplant. A kidney transplant is often the best treatment for kidney failure. A kidney transplant is a surgical procedure to place a healthy kidney from a donor into a person whose kidneys no longer function properly. This study is for people who will receive a kidney transplant from a very well matched, living blood relative. The immune system is the body's defense system against illness. After transplant, the immune system will think that the new kidney is a foreign invader and will try to attack or reject the transplanted kidney. Immunosuppressive drugs protect the transplanted kidney by suppressing the immune system. People who have kidney transplants must take immunosuppressive drug for the rest of their lives. If they stop, their immune system may reject the transplanted kidney. Immunosuppressive drugs make it hard for the body to fight off infections. In addition, they can cause high blood pressure, kidney damage, plaque build-up in the blood vessels, high cholesterol, diabetes and bone disease. They may also make the body more likely to get some types of cancer (mainly cancer of the white blood cells and/or skin) and other serious side effects. Because of the side effects of immunosuppressive drugs, an important goal of transplant research is to allow people to accept their transplanted organ without always having to take immunosuppressive drugs. This is called tolerance. The RESTARRT study is testing a combination of two medications, rituximab and anti-thymocyte globulin (ATG), to see if they can help people reduce or eliminate the need for life-long immunosuppressive medications. ATG has been used for over 10 years to treat transplant rejection; rituximab is used to treat rheumatoid arthritis and two types of cancer. ATG works on immune cells called 'T cells' that are involved in transplant rejection, while rituximab works on a different type of cell called 'B cells.' Researchers hope that targeting both these cell types at the same time will help reset the immune system so that it accepts the transplanted kidney. Frequent visits are required during the first two months of the study. Then, study visits take place about every 4 weeks, but more often (every 2 weeks) when reducing medication doses. After two years, participants will be asked to return for check-ups every 3 months. Study visits may include consultations with the transplant doctors, physical exam, blood and/or urine samples and kidney biopsies at several times during the study. In all, participation could last up to 4 years. All study-related medications and tests are provided at no charge to the patient.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Renal Transplant Recipients

Interventions

ATGDRUG

1.5 mg/kg IV infusion on day of transplant, and 3 additional on days 2 through 7 after transplant.

RituximabDRUG

375 mg/m\^2 IV infusion on day -6 before transplant and on day 1 after transplant.

TacrolimusDRUG

Taken orally. Tacrolimus dose adjusted to maintain target blood levels of 6-10 ng/mL.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Recipient of a first renal allograft from a single haplotype matched or greater living related donor who is no older than 65, or a second degree relative with an Human Leukocyte Antigen(HLA) type that is consistent with a single haplotype match with the recipient. * Demonstration of absence of anti-HLA antibodies using solid phase micro particle technology (by Luminex® phenotype panel or Luminex single antigen bead test) performed 7 days or less prior to the first dose of rituximab, as assessed by local laboratories.No evidence of anti-HLA antibodies in current or past sera.Negative T- and B-cell crossmatch as determined by flow cytometric assay measured 7 days or less prior to the first dose of rituximab. * Single-organ recipients (kidney only). * Serologic evidence of prior exposure to Epstein-Barr virus (EBV). * For women of childbearing potential: a negative serum or urine pregnancy test with sensitivity less than 50 mIU/m within 72 hours before the start of study medication. * Use of FDA-approved methods of contraception (those with less than a 5% failure rate) by all participants from the time that study treatment begins until 104 weeks (24 months) after renal transplantation. * Ability to receive oral medication. * Ability to understand and provide informed consent. Exclusion Criteria: * Recipient of a kidney from a donor who is older than 65 years. * History of cancer within the last 5 years, except for nonmelanoma skin cell cancers cured by local resection and cervical carcinoma in situ. * Women who are breastfeeding. * Uncontrolled hyperlipidemia (total serum cholesterol more than 300 mg/dL and/or triglycerides more than 400 mg/dL). * Platelet count less than 100,000/μL at study entry. * Seropositivity for HIV-1, Hepatitis C virus (HCV) (confirmed by HCV PCR), hepatitis B surface antigen, or Hepatitis B virus (HBV) core antibody (confirmed by HBV PCR). * Active tuberculosis (TB) within the previous 3 years regardless of treatment history for TB. Participants with a known positive purified protein derivative (PPD) or positive Quantiferon assay will not be eligible for the study unless they have completed treatment for latent TB and have a negative chest x-ray at the time of enrollment. PPD testing or Quantiferon testing done within 52 weeks before transplant is acceptable as long as there is documentation of the results. Prior recipients of a Bacille Calmette-Guérin vaccination (BCG) are not exempt. * Underlying renal disease with a high risk of disease recurrence in the transplanted kidney, including focal segmental glomerulosclerosis, types I or II membranoproliferative glomerulonephritis, and hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura. * The presence of any medical condition that the investigator deems incompatible with participation in the trial. * Known sensitivity to antithymocyte globulin, rituximab, tacrolimus, sirolimus, MMF, or corticosteroids. * Current use of systemic corticosteroids or antibody-based therapies (e.g., infliximab, adalimumab, or etanercept). * Use of any investigational drug within 30 days of transplantation. * Receipt of a live vaccine within 3 months of enrollment.

Locations (6)

University of California San Francisco Medical Center

San Francisco, California, United States

University of Maryland Medical Center

Baltimore, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Rogosin Institute/New York Presbyterian-Cornell

New York, New York, United States

Outcomes

Primary Outcomes

Percent of Participants Successfully Withdrawn From Immunosuppression and Remained Off Immunosuppression for at Least 52 Weeks

Participants are considered successfully withdrawn from immunosuppression if they remained off immunosuppression for at least 52 weeks without evidence of rejection, as determined by a biopsy performed 52 weeks after completion of immunosuppression withdrawal. All participants who failed to complete immunosuppression withdrawal, regardless of reason, or failed to have a biopsy 52 weeks after completion of immunosuppression withdrawal, were considered to have failed. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval.

Time frame: Transplantation through 52 weeks after discontinuation of all immunosuppression

Secondary Outcomes

Percent of Transplanted Participants Who Remain Off Immunosuppression for at Least 52 Weeks Including Those in Whom the 52 Week Biopsy Was Not Performed

Participants are considered successfully withdrawn from immunosuppression if they remained off immunosuppression for at least 52 weeks without evidence of rejection. A biopsy performed 52 weeks after completion of immunosuppression withdrawal confirmed that there was no sub-clinical evidence of rejection. This result considers a participant off all immunosuppression for at least 52 weeks with or without the confirmatory week 52 biopsy as a success. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval.

Time frame: Transplantation through 52 weeks after discontinuation of all immunosuppression

Percent of Transplanted Participants Who Remain Off Immunosuppression for the Duration of the Study as Defined as Completion of All Schedules of Events/Followed Through August 25, 2017

Participants that remained off all immunosuppression through the completion of study participation. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval.

Time frame: Transplantation through study completion (up to 4.4 years post-transplant)

Percent of Transplanted Participants Who Achieve Sirolimus Monotherapy Within 52 Weeks Post-transplant

Data from ClinicalTrials.gov

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Taken orally. Initial dose, 2 mg daily on day 10 post-transplant, subsequently adjusted to achieve trough levels of 8-12 ng/mL through week 56. Sirolimus withdrawal will be initiated between week 56 and week 88 in eligible participants.

MMFDRUG

1 g twice daily on days 0 through 12

Hospital at the University of Pennsylvania

Philadelphia, Pennsylvania, United States

University of Wisconsin

Madison, Wisconsin, United States

Participants that were treated with only sirolimus within 52 weeks after transplantation in those who could tolerant sirolimus. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval.

Time frame: Transplantation through 52 weeks post-transplantation

Percent of Transplanted Participants Who Achieve MMF or Mycophenolic Acid Monotherapy Within 52 Weeks Post-transplant in Those Participants Intolerant of Sirolimus

Participants that were treated with only mycophenolate mofetil (MMF) or mycophenolic acid within 52 weeks after transplantation in those who could not tolerate sirolimus. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval.

Time frame: Transplantation through 52 weeks post-transplantation

Percent of Transplanted Participants Who Achieve Either Sirolimus Monotherapy or Monotherapy on a Mycophenolic Compound Within 52 Weeks Post-transplant

Participants that were treated with only sirolimus or treated with only mycophenolate mofetil (MMF) or mycophenolic acid within 52 weeks after transplantation. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval.

Time frame: Transplantation through 52 weeks post-transplantation

Immunosuppression-free Duration in Days, Defined as Time From Completion of Immunosuppression Withdrawal to End of Trial Participation or to Time of Restarting Immunosuppression

Time (in days) from when the participant is off all immunosuppression to the end of trial participation or re-initiation of immunosuppression, whichever is earliest.