Brief Summary

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Official Title: "Immunosuppression With Antithymocyte Globulin, Rituximab, Tacrolimus, Mycophenolate Mofetil and Sirolimus, Followed by Immunosuppression Withdrawal, in Living-donor Renal Transplant Recipients (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.

• Study Type: Interventional
• Study Design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
• Study Primary Completion Date: April 2016

Detailed Clinical Trial 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.

Interventions Used in this Clinical Trial

• Drug: ATG
  • 1.5 mg/kg IV infusion on days 0,1,2 and 3 following transplant
• Drug: Rituximab
  • 375 mg/m2 IV infusion on days 0 and 7 following transplant
• Drug: Tacrolimus
  • Taken orally. Initial tacrolimus dose will be 2 mg, twice daily, subsequently adjusted to maintain target blood levels of 4-8 ng/mL. Tacrolimus will be withdrawn over 4 to 8 weeks in eligible participants beginning at week 26 post-transplant.
• 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 72 in eligible participants.
• Drug: MMF
  • 1 g twice daily on days 0 through 12

Arms, Groups and Cohorts in this Clinical Trial

• 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 80. Sirolimus withdrawal must be completed in no fewer than 12 weeks and no more than 26 weeks.

Outcome Measures for this Clinical Trial

Primary Measures

• Proportion of subjects successfully withdrawn from immunosuppression
  • Time Frame: 52 weeks after stopping all immunosuppression
    Safety Issue?: No

Secondary Measures

• The proportion of participants who achieve sirolimus monotherapy
  • Time Frame: 52 weeks post-transplant
    Safety Issue?: No
• 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 Issue?: No
• Safety endpoints, stratified by sirolimus withdrawal status
  • Time Frame: 56 weeks - 4.5 years
    Safety Issue?: Yes
• The proportion of participants who achieve either sirolimus or monotherapy
  • Time Frame: 52 weeks post transplant
    Safety Issue?: No
• Immunosuppression-free duration
  • Time Frame: 56 weeks - 4.5 years
    Safety Issue?: No
• Rejection-free duration
  • Time Frame: 56 weeks - 4.5 years
    Safety Issue?: No
• Proportion of participants with graft loss
  • Time Frame: Day 0 - 4.5 years
    Safety Issue?: No
• The proportion of participants who die
  • Time Frame: Day 0 - 4.5 years
    Safety Issue?: No
• The proportion of participants with acute rejection
  • Time Frame: Day 0 - 4.5 years
    Safety Issue?: No
• The histological severity of biopsies demonstrating acute rejection as measured by Banff Grade
  • Time Frame: Day 0 - 4.5 years
    Safety Issue?: No
• The proportion of participants with chronic allograft nephropathy
  • Time Frame: Day 0 - 4.5 years
    Safety Issue?: No
• Time from transplant to the first episode of acute rejection requiring treatment
  • Time Frame: Day 0 - 4.5 years
    Safety Issue?: No
• The proportion of participants requiring antilymphocyte therapy (OKT3, ATG) for an acute rejection
  • Time Frame: Day 0 - 4.5 years
    Safety Issue?: No
• 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
    Safety Issue?: No
• Renal function as measured by calculated creatinine clearance using the CKDEPI calculator
  • Time Frame: Day 0 - 4.5 years
    Safety Issue?: No
• Safety, including, renal function, blood pressure, cholesterol level, and glucose control
  • Time Frame: Day 0 - 4.5 years
    Safety Issue?: Yes

Criteria for Participation in this Clinical Trial

Inclusion Criteria

• Recipient of a first renal allograft from a single haplotype matched or greater living related donor who is no older than 65.
• Absence of donor‐specific antibody (DSA), as determined by Luminex® phenotype panel or Luminex single antigen bead test performed 30 days or less prior to the first dose of rituximab. - Negative T‐ and B‐cell crossmatch as determined by flow cytometric assay measured within 4 weeks prior to transplant.
• No evidence of anti-HLA antibodies in current or past sera.
• 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 3% 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, 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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial: No

Clinical Trial Investigator Information

• Lead Sponsor
  • National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborator
  • Immune Tolerance Network (ITN)
• Provider of Information About this Clinical Study
  • Sponsor
• Overall Official(s)
  • James Markmann, MD, PhD, Principal Investigator, Massachusetts General Hospital