This trial is active, not recruiting.

Condition acute kidney injury
Treatments atg, rituximab, tacrolimus, sirolimus, mmf
Phase phase 0
Targets CD20, mTOR, FKBP-12
Sponsor National Institute of Allergy and Infectious Diseases (NIAID)
Collaborator Immune Tolerance Network (ITN)
Start date June 2011
End date December 2018
Trial size 10 participants
Trial identifier NCT01318915, DAIT ITN039ST


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.

United States No locations recruiting
Other countries No locations recruiting

Study Design

Endpoint classification safety/efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Study participants will undergo induction with rituximab and ATG and an initial maintenance therapy with tacrolimus, 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.
atg Thymoglobulin
1.5 mg/kg IV infusion on day of transplant, and 3 additional on days 2 through 7 after transplant.
rituximab Rituxan
375 mg/m^2 IV infusion on day -6 before transplant and on day 1 after transplant.
tacrolimus Prograf
Taken orally. Tacrolimus dose adjusted to maintain target blood levels of 6-10 ng/mL.
sirolimus Rapamune
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.
mmf mycophenolate mofetil
1 g twice daily on days 0 through 12

Primary Outcomes

Proportion of subjects successfully withdrawn from immunosuppression
time frame: 52 weeks after stopping all immunosuppression

Secondary Outcomes

The proportion of participants who achieve sirolimus monotherapy
time frame: 52 weeks post-transplant
The proportion of participants who achieve mycophenolate mofetil (MMF/Cellcept®) or mycophenolic acid (Myfortic ®) monotherapy in those participants intolerant of sirolimus.
time frame: 52 weeks post-transplant
Safety endpoints, stratified by sirolimus withdrawal status
time frame: 56 weeks - 4.5 years
The proportion of participants who achieve either sirolimus or monotherapy
time frame: 52 weeks post transplant
Immunosuppression-free duration
time frame: 56 weeks - 4.5 years
Rejection-free duration
time frame: 56 weeks - 4.5 years
Proportion of participants with graft loss
time frame: Day 0 - 4.5 years
The proportion of participants who die
time frame: Day 0 - 4.5 years
The proportion of participants with acute rejection
time frame: Day 0 - 4.5 years
The histological severity of biopsies demonstrating acute rejection as measured by Banff Grade
time frame: Day 0 - 4.5 years
The proportion of participants with chronic allograft nephropathy
time frame: Day 0 - 4.5 years
Time from transplant to the first episode of acute rejection requiring treatment
time frame: Day 0 - 4.5 years
The proportion of participants requiring antilymphocyte therapy (OKT3, ATG) for an acute rejection
time frame: Day 0 - 4.5 years
Incidence of adverse events, including incidence of post-transplant infections, wound complications, lymphocoele, post-transplant diabetes mellitus, and malignancies
time frame: Day 0 - 4.5 years
Renal function as measured by calculated creatinine clearance using the CKDEPI calculator
time frame: Day 0 - 4.5 years
Safety, including, renal function, blood pressure, cholesterol level, and glucose control
time frame: Day 0 - 4.5 years

Eligibility Criteria

Male or female participants from 18 years up to 65 years old.

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 HLA antigen 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 (confirmed by HCV PCR), hepatitis B surface antigen, or hepatitis B 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.

Additional Information

Official title Immunosuppression With Antithymocyte Globulin, Rituximab, Tacrolimus, Mycophenilate Mofetil and Sirolimus, Followed by Withdrawal of Immunosuppression, in Living-donor Renal Transplant Recipients
Principal investigator James Markmann, MD, PhD
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.
Trial information was received from ClinicalTrials.gov and was last updated in February 2016.
Information provided to ClinicalTrials.gov by National Institute of Allergy and Infectious Diseases (NIAID).