Research Study of ATG and Rituximab in Renal Transplantation (RESTARRT)
Acute Kidney Injury
Early Phase 1
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Immunosuppression With Antithymocyte Globulin, Rituximab, Tacrolimus, Mycophenilate Mofetil and Sirolimus, Followed by Withdrawal of Immunosuppression, in Living-donor Renal Transplant Recipients|
- Proportion of subjects successfully withdrawn from immunosuppression [ Time Frame: 52 weeks after stopping all immunosuppression ]defined as those who remain off immunosuppression for at least 52 weeks
- 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 ]
- Incidence of adverse events
- kidney function (measured by creatinine clearance)
- 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 ]only in subjects who complete sirolimus withdrawal
- Rejection-free duration [ Time Frame: 56 weeks - 4.5 years ]only in subjects who complete sirolimus withdrawal
- Proportion of participants with graft loss [ Time Frame: Day 0 - 4.5 years ]stratified by the following groups: 1) participants who attempt sirolimus withdrawal and succeed 2) participants who attempt sirolimus withdrawal but fail, and 3) participants who do not attempt sirolimus withdrawal
- The proportion of participants who die [ Time Frame: Day 0 - 4.5 years ]stratified by the following groups: 1) participants who attempt sirolimus withdrawal and succeed 2) participants who attempt sirolimus withdrawal but fail, and 3) participants who do not attempt sirolimus withdrawal
- The proportion of participants with acute rejection [ Time Frame: Day 0 - 4.5 years ]stratified by the following groups: 1) participants who attempt sirolimus withdrawal and succeed 2) participants who attempt sirolimus withdrawal but fail, and 3) participants who do not attempt sirolimus withdrawal
- 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 ]
|Study Start Date:||June 2011|
|Estimated Study Completion Date:||June 2020|
|Estimated Primary Completion Date:||December 2018 (Final data collection date for primary outcome measure)|
Experimental: Immunosuppressive Maintenance Withdrawal
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.
1.5 mg/kg IV infusion on day of transplant, and 3 additional on days 2 through 7 after transplant.
Other Names:Drug: Rituximab
375 mg/m^2 IV infusion on day -6 before transplant and on day 1 after transplant.
Other Name: RituxanDrug: Tacrolimus
Taken orally. Tacrolimus dose adjusted to maintain target blood levels of 6-10 ng/mL.
Other Names: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:Drug: MMF
1 g twice daily on days 0 through 12
Other Name: mycophenolate mofetil
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.
Please refer to this study by its ClinicalTrials.gov identifier: 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|
|Principal Investigator:||James Markmann, MD, PhD||Massachusetts General Hospital|