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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Collaborator:
Immune Tolerance Network (ITN)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT01318915
First received: March 15, 2011
Last updated: March 24, 2014
Last verified: March 2014
  Purpose

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 Intervention Phase
Acute Kidney Injury
Drug: ATG
Drug: Rituximab
Drug: Tacrolimus
Drug: Sirolimus
Drug: MMF
Phase 0

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
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

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Proportion of subjects successfully withdrawn from immunosuppression [ Time Frame: 52 weeks after stopping all immunosuppression ] [ Designated as safety issue: No ]
    defined as those who remain off immunosuppression for at least 52 weeks


Secondary Outcome Measures:
  • The proportion of participants who achieve sirolimus monotherapy [ Time Frame: 52 weeks post-transplant ] [ Designated as 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 ] [ Designated as safety issue: No ]
  • Safety endpoints, stratified by sirolimus withdrawal status [ Time Frame: 56 weeks - 4.5 years ] [ Designated as safety issue: Yes ]
    • 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 ] [ Designated as safety issue: No ]
  • Immunosuppression-free duration [ Time Frame: 56 weeks - 4.5 years ] [ Designated as safety issue: No ]
    only in subjects who complete sirolimus withdrawal

  • Rejection-free duration [ Time Frame: 56 weeks - 4.5 years ] [ Designated as safety issue: No ]
    only in subjects who complete sirolimus withdrawal

  • Proportion of participants with graft loss [ Time Frame: Day 0 - 4.5 years ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 chronic allograft nephropathy [ Time Frame: Day 0 - 4.5 years ] [ Designated as safety issue: No ]
    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

  • Time from transplant to the first episode of acute rejection requiring treatment [ Time Frame: Day 0 - 4.5 years ] [ Designated as safety issue: No ]
    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 requiring antilymphocyte therapy (OKT3, ATG) for an acute rejection [ Time Frame: Day 0 - 4.5 years ] [ Designated as safety issue: No ]
    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

  • 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 ] [ Designated as safety issue: No ]
    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

  • Renal function as measured by calculated creatinine clearance using the CKDEPI calculator [ Time Frame: Day 0 - 4.5 years ] [ Designated as safety issue: No ]
    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

  • Safety, including, renal function, blood pressure, cholesterol level, and glucose control [ Time Frame: Day 0 - 4.5 years ] [ Designated as safety issue: Yes ]
    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


Estimated Enrollment: 10
Study Start Date: June 2011
Estimated Study Completion Date: October 2018
Estimated Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: ATG
1.5 mg/kg IV infusion on days 0,1,2 and 3 following transplant
Other Names:
  • Thymoglobulin
  • Antithymocyte globulin
Drug: Rituximab
375 mg/m2 IV infusion on days 0 and 7 following transplant
Other Name: Rituxan
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.
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 72 in eligible participants.
Other Names:
  • Rapamune
  • Rapamycin
Drug: MMF
1 g twice daily on days 0 through 12
Other Name: mycophenolate mofetil

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

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 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.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01318915

Locations
United States, California
University of California San Francisco Medical Center Recruiting
San Francisco, California, United States, 94143
Contact: Joan McElroy    415-353-8465    Joan.McElroy@ucsfmedctr.org   
Contact: Mehdi Tavakol    415- 476-0789    mehdi.tavakol@ucsfmedctr.org   
Principal Investigator: Andrew Posselt, MD, PhD         
United States, Maryland
University of Maryland Medical Center Recruiting
Baltimore, Maryland, United States, 21201
Contact: Minori Kinjo    410-328-0303    mkinjo@smail.umaryland.edu   
Principal Investigator: Jonathan Bromberg, MD, PhD         
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Kerry Crisalli    617-643-4087    kcrisalli@partners.org   
Principal Investigator: James Markmann, MD, PhD         
United States, New York
Rogosin Institute/New York Presbyterian-Cornell Recruiting
New York, New York, United States, 10021
Contact: Shaquanda Lippman    646-898-2753    shl9081@nyp.org   
Principal Investigator: Choli Hartono, MD         
United States, Pennsylvania
Hospital at the University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Jennifer Trofe Clark    215-349-8714    Jennifer.Trofe-Clark@uphs.upenn.edu   
Principal Investigator: Ali Naji, MD, PhD         
Sponsors and Collaborators
Immune Tolerance Network (ITN)
Investigators
Principal Investigator: James Markmann, MD, PhD Massachusetts General Hospital
  More Information

Additional Information:
No publications provided

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01318915     History of Changes
Other Study ID Numbers: DAIT ITN039ST
Study First Received: March 15, 2011
Last Updated: March 24, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Living donor transplant
Living-donor
Kidney transplantation
Immunosuppression
Graft rejection
Graft loss
Renal transplant
Transplantation
kidney disease
Renal disease
Organ transplant

Additional relevant MeSH terms:
Acute Kidney Injury
Wounds and Injuries
Renal Insufficiency
Kidney Diseases
Urologic Diseases
Antilymphocyte Serum
Mycophenolate mofetil
Sirolimus
Everolimus
Tacrolimus
Rituximab
Mycophenolic Acid
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Immunosuppressive Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Anti-Bacterial Agents
Anti-Infective Agents
Antifungal Agents
Antirheumatic Agents

ClinicalTrials.gov processed this record on August 21, 2014