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Immunosuppression With Antithymocyte Globulin, Rituximab, Tacrolimus, Mycophenolate Mofetil and Sirolimus, Followed by Immunosuppression Withdrawal, in Living-donor Renal Transplant Recipients (ITN039ST)

Phase 0
18 Years
65 Years
Open (Enrolling)
Acute Kidney Injury

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Trial Information

Immunosuppression With Antithymocyte Globulin, Rituximab, Tacrolimus, Mycophenolate Mofetil and Sirolimus, Followed by Immunosuppression Withdrawal, in Living-donor Renal Transplant Recipients (ITN039ST)

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.

Inclusion Criteria:

1. Recipient of a first renal allograft from a single haplotypematched or greater living
related donor. Also acceptable as a kidney donor is a second degree relative with an
HLA antigen type that is consistent with a single haplotype match with the recipient.

2. 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. A flow cytometry PRA may be performed in addition to the above, but is
not required. If performed, the flow cytometry PRA results should be documented
separately on the eCRF.

3. No evidence of anti-HLA antibodies in current or past sera. If an investigator feels
that a potential study participant, despite having evidence of anti-HLA antibodies in
past sera, should be considered for eligibility, then the investigator must request
that the candidate's data is reviewed by the adjudication committee.

4. Negative T and B cell flow crossmatches with the designated donor performed 7 days or
less prior to the first dose of rituximab, as assessed by local laboratories. If one
or more of the crossmatches is positive, the participant will be considered a screen
failure unless combined results of antibody and cross match testing implicate a
non-HLA antibody as the cause of the positive flow crossmatch. In this case, the
Protocol Chair must approve the participant as a screening success after consultation
with the local HLA Laboratory Director.

5. Single-organ recipients (kidney only).

6. Serologic evidence of prior exposure to Epstein-Barr virus (EBV).

7. 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.

8. Use of FDA-approved methods of contraception (those with less than a 5% failure rate)
or abstinence by all transplanted participants from the time that study treatment
begins until 104 weeks (24 months) after renal transplantation.

9. Ability to receive oral medication.

10. Ability to understand and provide informed consent. Kidney donors must meet all of
the following criteria to be eligible to participate in this study:

11. Age no greater than 65 years.

12. Ability to understand and provide informed consent.

Exclusion Criteria:

1. History of cancer within the last 5 years, except for nonmelanoma skin cell cancers
cured by local resection and cervical carcinoma in situ.

2. Women who are breastfeeding.

3. Uncontrolled hyperlipidemia (total serum cholesterol more than 300 mg/dL or
triglycerides more than 400 mg/dL).

4. Platelet count less than 100,000/μL at the screening visit.

5. Positive serology for HIV-1, hepatitis C virus, hepatitis B surface antigen, or
hepatitis B core antigen. Positive serologies for HCV or HBV must be confirmed by HCV
or HBV PCR respectively; as assessed by central laboratory assessments.

6. Active TB within 3 years of enrollment regardless of treatment history for TB.
Participants with a known positive purified protein derivative (PPD) or positive
QuantiFERON® (QFT) assay will not be eligible for the study unless they have
completed treatment for latent TB and have a negative chest x-ray. PPD or QFT 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 (BCG)
vaccination are not exempt.

7. Underlying renal disease with a high risk of disease recurrence in the transplanted
kidney, including focal segmental glomerulosclerosis, type I or II
membranoproliferative glomerulonephritis and hemolytic-uremic syndrome/thrombotic
thrombocytopenic purpura.

8. The presence of any medical condition that the investigator deems incompatible with
participation in the trial.

9. Known sensitivity to ATG, rituximab, tacrolimus, MMF, sirolimus, or corticosteroids.

10. Current use of systemic corticosteroids or antibody-based therapies (e.g.,
infliximab, adalimumab, or etanercept).

11. Use of investigational drug, other than the study medications specified by the
protocol, within 30 days of transplantation.

12. Receipt of a live vaccine within 30 days of transplantation.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Proportion of subjects successfully withdrawn from immunosuppression

Outcome Description:

defined as those who remain off immunosuppression for at least 52 weeks

Outcome Time Frame:

52 weeks after stopping all immunosuppression

Safety Issue:


Principal Investigator

James Markmann, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Massachusetts General Hospital


United States: Federal Government

Study ID:




Start Date:

June 2011

Completion Date:

October 2018

Related Keywords:

  • Acute Kidney Injury
  • Kidney transplantation
  • Immunosuppression
  • Graft rejection
  • Graft loss
  • Renal transplant
  • Transplantation
  • kidney disease
  • Renal disease
  • Organ transplant
  • Living donor transplant
  • Living-donor
  • Acute Kidney Injury



Massachusetts General HospitalBoston, Massachusetts  02114-2617
University of Maryland Medical CenterBaltimore, Maryland  21201-1595
University of California San Francisco Medical CenterSan Francisco, California  94143
Hospital at the University of PennsylvaniaPhiladelphia, Pennsylvania  19104
Rogosin Institute/New York Presbyterian-CornellNew York, New York  10021