Research Study of ATG and Rituximab in Renal Transplantation (RESTARRT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01318915
Recruitment Status : Terminated (The stopping rule for incidence of acute rejection was met.)
First Posted : March 21, 2011
Results First Posted : October 4, 2017
Last Update Posted : December 2, 2017
Immune Tolerance Network (ITN)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

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.

Condition or disease Intervention/treatment Phase
Renal Transplant Recipients Drug: ATG Drug: Rituximab Drug: Tacrolimus Drug: Sirolimus Drug: MMF Early Phase 1

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Immunosuppression With Antithymocyte Globulin, Rituximab, Tacrolimus, Mycophenolate Mofetil and Sirolimus, Followed by Withdrawal of Immunosuppression, in Living-donor Renal Transplant Recipients
Actual Study Start Date : July 25, 2011
Actual Primary Completion Date : June 17, 2016
Actual Study Completion Date : August 25, 2017

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Induction (Rituximab and ATG)
Study participants will undergo induction with rituximab and ATG and an initial maintenance therapy with tacrolimus, mycophenolate mofetil (MMF) and sirolimus. MMF will be discontinued on day 12. Participants will be evaluated for eligibility for tacrolimus withdrawal which must be initiated between weeks 26 and 38. Tacrolimus withdrawal must be completed in no fewer than 4 weeks and no more than 8 weeks. Then after at least 26 weeks on sirolimus monotherapy, participants will be evaluated for eligibility for sirolimus withdrawal which must be initiated between weeks 56 and 88. Sirolimus withdrawal must be completed in no fewer than 12 weeks and no more than 26 weeks.
Drug: ATG
1.5 mg/kg IV infusion on day of transplant, and 3 additional on days 2 through 7 after transplant.
Other Names:
  • Thymoglobulin
  • Antithymocyte globulin

Drug: Rituximab
375 mg/m^2 IV infusion on day -6 before transplant and on day 1 after transplant.
Other Name: Rituxan

Drug: Tacrolimus
Taken orally. Tacrolimus dose adjusted to maintain target blood levels of 6-10 ng/mL.
Other Names:
  • Prograf
  • FK-506
  • Fujimycin

Drug: Sirolimus
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.
Other Names:
  • Rapamune
  • Rapamycin

Drug: MMF
1 g twice daily on days 0 through 12
Other Name: mycophenolate mofetil

Primary Outcome Measures :
  1. Percentage of Participants Successfully Withdrawn From Immunosuppression and Remain Off Immunosuppression for at Least 52 Weeks. [ Time Frame: Transplantation through 52 weeks after stopping all immunosuppression. ]
    Participants are considered as successfully withdrawn from immunosuppression if they remain 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 fail to complete immunosuppression withdrawal, regardless of reason, or fail to have a biopsy 52 weeks after completion of immunosuppression withdrawal will be considered to have failed. The endpoint will be summarized with a two-sided, 95% exact binomial confidence interval.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01318915

United States, California
University of California San Francisco Medical Center
San Francisco, California, United States, 94143
United States, Maryland
University of Maryland Medical Center
Baltimore, Maryland, United States, 21201
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
United States, New York
Rogosin Institute/New York Presbyterian-Cornell
New York, New York, United States, 10021
United States, Pennsylvania
Hospital at the University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Wisconsin
University of Wisconsin
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Immune Tolerance Network (ITN)
Principal Investigator: James Markmann, MD, PhD Massachusetts General Hospital

Additional Information:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID) Identifier: NCT01318915     History of Changes
Other Study ID Numbers: DAIT ITN039ST
First Posted: March 21, 2011    Key Record Dates
Results First Posted: October 4, 2017
Last Update Posted: December 2, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The plan is to provide data access to the public in the Immunology Database and Analysis Portal (ImmPort, upon completion of the study. ImmPort is a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Kidney transplantation
Living donor transplant
Graft rejection
Graft loss
Induction with rituximab and ATG
Immunosuppression (IS)

Additional relevant MeSH terms:
Mycophenolic Acid
Antilymphocyte Serum
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Immunosuppressive Agents
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antibiotics, Antitubercular
Antitubercular Agents