Clinical trial NCT01318915: Research Study of ATG and Rituximab in Renal Transplantation
Official title: Immunosuppression With Antithymocyte Globulin, Rituximab, Tacrolimus, Mycophenolate Mofetil and Sirolimus, Followed by Withdrawal of Immunosuppression, in Living-donor Renal Transplant Recipients
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: EARLY_PHASE1
Conditions: Renal Transplant Recipients
Keywords: Kidney transplantation
Living donor transplant
Graft rejection
Graft loss
Induction with rituximab and ATG
Immunosuppression (IS)
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Immune Tolerance Network (ITN)
First posted: 2011-03-21
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percent of Participants Successfully Withdrawn From Immunosuppression and Remained Off Immunosuppression for at Least 52 Weeks
timeFrame: Transplantation through 52 weeks after discontinuation of all immunosuppression
Secondary outcomes:
measure: Percent of Transplanted Participants Who Remain Off Immunosuppression for at Least 52 Weeks Including Those in Whom the 52 Week Biopsy Was Not Performed
timeFrame: Transplantation through 52 weeks after discontinuation of all immunosuppression
measure: 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
timeFrame: Transplantation through study completion (up to 4.4 years post-transplant)
measure: Percent of Transplanted Participants Who Achieve Sirolimus Monotherapy Within 52 Weeks Post-transplant
timeFrame: Transplantation through 52 weeks post-transplantation
measure: Percent of Transplanted Participants Who Achieve MMF or Mycophenolic Acid Monotherapy Within 52 Weeks Post-transplant in Those Participants Intolerant of Sirolimus
timeFrame: Transplantation through 52 weeks post-transplantation
measure: Percent of Transplanted Participants Who Achieve Either Sirolimus Monotherapy or Monotherapy on a Mycophenolic Compound Within 52 Weeks Post-transplant
timeFrame: Transplantation through 52 weeks post-transplantation
measure: Immunosuppression-free Duration in Days, Defined as Time From Completion of Immunosuppression Withdrawal to End of Trial Participation or to Time of Restarting Immunosuppression
timeFrame: Transplantation through end of trial participation (up to 4.4 years post-transplant)
measure: Time From Completion of Immunosuppression Withdrawal to First Episode of Acute Rejection or Presumed Acute Rejection
timeFrame: Transplantation through end of trial participation (up to 4.4 years post-transplant)
measure: Time From Completion of Immunosuppression Withdrawal to First Diagnosis of Chronic T Cell Mediated or Antibody-mediated Rejection
timeFrame: Transplantation through end of trial participation (up to 4.4 years post-transplant)
measure: Percent of Transplanted Participants With Graft Loss
timeFrame: Transplantation through end of trial participation (up to 4.4 years post-transplant)
measure: Percent of Transplant Participants Who Died
timeFrame: Transplantation through end of trial participation (up to 4.4 years post-transplant)
measure: Percent of Transplanted Participants With Acute Rejection or Presumed Acute Rejection
timeFrame: Transplantation through end of trial participation (up to 4.4 years post-transplant)
measure: Histological Severity of Biopsies Demonstrating Acute Rejection as Measured by Banff 2007 Grade
timeFrame: Transplantation through end of trial participation (up to 4.4 years post-transplant)
measure: Percent of Participants With Chronic T Cell-mediated or Antibody-mediated Rejection
timeFrame: Transplantation through end of trial participation (up to 4.4 years post-transplant)
measure: Time From Transplant to the First Episode of Acute Rejection Requiring Treatment
timeFrame: Transplantation through end of trial participation (up to 4.4 years post-transplant)
measure: Percent of Participants Requiring Anti-lymphocyte Therapy (OKT3, ATG) for an Acute Rejection Event
timeFrame: Transplantation through end of trial participation (up to 4.4 years post-transplant)
measure: Number of Adverse Events, Including Number of Post-transplant Infections, Wound Complications, Lymphocoele, Post-transplant Diabetes Mellitus, and Malignancies
timeFrame: Transplantation through end of trial participation (up to 4.4 years post-transplant)
measure: Participant Renal Function as Measured by GFR Using CKD-EPI
timeFrame: 26, 52, 104, 156, and 208 Weeks Post-Transplant
measure: Participant Systolic Blood Pressure Over Time
timeFrame: 26, 52, 104, 156, and 208 Weeks Post-Transplant
measure: Participant Diastolic Blood Pressure Over Time
timeFrame: 26, 52, 104, 156, and 208 Weeks Post-Transplant
measure: Participant Total Cholesterol Over Time
timeFrame: 26, 52, 104, 156, and 208 Weeks Post-Transplant
measure: Participant Glucose Level Over Time
timeFrame: 26, 52, 104, 156, and 208 Weeks Post-Transplant
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco Medical Center
state: California
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: New York
country: United States
facility: Rogosin Institute/New York Presbyterian-Cornell
state: New York
city: Philadelphia
country: United States
facility: Hospital at the University of Pennsylvania
state: Pennsylvania
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: Massachusetts General Hospital
name: James Markmann, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, Halloran PF, Baldwin W, Banfi G, Collins AB, Cosio F, David DS, Drachenberg C, Einecke G, Fogo AB, Gibson IW, Glotz D, Iskandar SS, Kraus E, Lerut E, Mannon RB, Mihatsch M, Nankivell BJ, Nickeleit V, Papadimitriou JC, Randhawa P, Regele H, Renaudin K, Roberts I, Seron D, Smith RN, Valente M. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. 2008 Apr;8(4):753-60. doi: 10.1111/j.1600-6143.2008.02159.x. Epub 2008 Feb 19.