Research Study of ATG and Rituximab in Renal Transplantation

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Renal Transplant Recipients

Intervention / Treatment
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* Drug: ATG
* Drug: Rituximab
* Drug: Tacrolimus
* Drug: Sirolimus
* Drug: MMF


Participation Criteria
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Eligibility Criteria
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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 Human Leukocyte Antigen(HLA) 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 (HCV) (confirmed by HCV PCR), hepatitis B surface antigen, or Hepatitis B virus (HBV) 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Induction (Rituximab and ATG)<br>Study participants will undergo induction with rituximab and ATG and an initial maintenance therapy with tacrolimus, mycophenolate mofetil (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. | Drug: ATG<br>* 1.5 mg/kg IV infusion on day of transplant, and 3 additional on days 2 through 7 after transplant.<br>* Other names: Antithymocyte globulin;Drug: Rituximab<br>* 375 mg/m^2 IV infusion on day -6 before transplant and on day 1 after transplant.<br>* Other names: Rituxan;Drug: Tacrolimus<br>* Taken orally. Tacrolimus dose adjusted to maintain target blood levels of 6-10 ng/mL.<br>* Other names: Fujimycin;Drug: Sirolimus<br>* 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.<br>* Other names: Rapamycin;Drug: MMF<br>* 1 g twice daily on days 0 through 12<br>* Other names: mycophenolate mofetil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants Successfully Withdrawn From Immunosuppression and Remained Off Immunosuppression for at Least 52 Weeks | Participants are considered successfully withdrawn from immunosuppression if they remained off immunosuppression for at least 52 weeks without evidence of rejection, as determined by a biopsy performed 52 weeks after completion of immunosuppression withdrawal. All participants who failed to complete immunosuppression withdrawal, regardless of reason, or failed to have a biopsy 52 weeks after completion of immunosuppression withdrawal, were considered to have failed. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval. | Transplantation through 52 weeks after discontinuation of all immunosuppression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Transplanted Participants Who Remain Off Immunosuppression for at Least 52 Weeks Including Those in Whom the 52 Week Biopsy Was Not Performed | Participants are considered successfully withdrawn from immunosuppression if they remained off immunosuppression for at least 52 weeks without evidence of rejection. A biopsy performed 52 weeks after completion of immunosuppression withdrawal confirmed that there was no sub-clinical evidence of rejection. This result considers a participant off all immunosuppression for at least 52 weeks with or without the confirmatory week 52 biopsy as a success. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval. | Transplantation through 52 weeks after discontinuation of all immunosuppression | 
| Percent of Transplanted Participants Who Remain Off Immunosuppression for the Duration of the Study as Defined as Completion of All Schedules of Events/Followed Through August 25, 2017 | Participants that remained off all immunosuppression through the completion of study participation. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval. | Transplantation through study completion (up to 4.4 years post-transplant) | 
| Percent of Transplanted Participants Who Achieve Sirolimus Monotherapy Within 52 Weeks Post-transplant | Participants that were treated with only sirolimus within 52 weeks after transplantation in those who could tolerant sirolimus. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval. | Transplantation through 52 weeks post-transplantation | 
| Percent of Transplanted Participants Who Achieve MMF or Mycophenolic Acid Monotherapy Within 52 Weeks Post-transplant in Those Participants Intolerant of Sirolimus | Participants that were treated with only mycophenolate mofetil (MMF) or mycophenolic acid within 52 weeks after transplantation in those who could not tolerate sirolimus. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval. | Transplantation through 52 weeks post-transplantation | 
| Percent of Transplanted Participants Who Achieve Either Sirolimus Monotherapy or Monotherapy on a Mycophenolic Compound Within 52 Weeks Post-transplant | Participants that were treated with only sirolimus or treated with only mycophenolate mofetil (MMF) or mycophenolic acid within 52 weeks after transplantation. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval. | Transplantation through 52 weeks post-transplantation | 
| Immunosuppression-free Duration in Days, Defined as Time From Completion of Immunosuppression Withdrawal to End of Trial Participation or to Time of Restarting Immunosuppression | Time (in days) from when the participant is off all immunosuppression to the end of trial participation or re-initiation of immunosuppression, whichever is earliest. | Transplantation through end of trial participation (up to 4.4 years post-transplant) | 
| Time From Completion of Immunosuppression Withdrawal to First Episode of Acute Rejection or Presumed Acute Rejection | Time (in days) from when the participant is off all immunosuppression to the first episode of biopsy proven or presumed acute rejection. | Transplantation through end of trial participation (up to 4.4 years post-transplant) | 
| Time From Completion of Immunosuppression Withdrawal to First Diagnosis of Chronic T Cell Mediated or Antibody-mediated Rejection | Time (in days) from the time the participant is off all immunosuppression to the first episode of chronic T cell mediated or chronic antibody-mediated rejection. This assessment also includes progressive interstitial fibrosis/tubular atrophy (IF/TA), transplant glomerulopathy or chronic obliterative arteriopathy without an alternative, non-rejection related cause. | Transplantation through end of trial participation (up to 4.4 years post-transplant) | 
| Percent of Transplanted Participants With Graft Loss | A participant is considered to have graft loss when the donated kidney needs to be removed, the participant is retransplanted with another donor kidney, or chronic dialysis is instituted. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval. | Transplantation through end of trial participation (up to 4.4 years post-transplant) | 
| Percent of Transplant Participants Who Died | Death after receiving a kidney transplant. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval. | Transplantation through end of trial participation (up to 4.4 years post-transplant) | 
| Percent of Transplanted Participants With Acute Rejection or Presumed Acute Rejection | Participants with either biopsy proven acute rejection per Banff guidelines or participants that were treated for acute rejection in the absence of a biopsy. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval. | Transplantation through end of trial participation (up to 4.4 years post-transplant) | 
| Histological Severity of Biopsies Demonstrating Acute Rejection as Measured by Banff 2007 Grade | Biopsy-confirmed 1.) acute cellular rejection and 2.) acute antibody-mediated rejection was classified according to Banff 2007 criteria of renal allograft pathology for renal allograft rejection. A Banff result of indeterminate was not classified as rejection. Acute cellular rejection occurs when lesions at the site of the graft characteristically are infiltrated with large numbers of lymphocytes and macrophages that cause tissue damage. Acute cellular rejection is defined as a grade ≥ IA. Severity is graded as IA, IB, IIA, IIB, or III, with IA being the mildest form of cellular rejection and III being the most severe. Acute antibody-mediated rejection-or humoral rejection-is defined as a grade ≥1. Severity is graded as I, II, or III, with I being the mildest form of antibody-mediated rejection and III being the most severe. | Transplantation through end of trial participation (up to 4.4 years post-transplant) | 
| Percent of Participants With Chronic T Cell-mediated or Antibody-mediated Rejection | This assessment included participants who experienced chronic T cell-mediated rejection or chronic antibody mediated rejection as well as progressive interstitial fibrosis/tubular atrophy (IF/TA), transplant glomerulopathy or chronic obliterative arteriopathy without an alternative, non-rejection-related cause. | Transplantation through end of trial participation (up to 4.4 years post-transplant) | 
| Time From Transplant to the First Episode of Acute Rejection Requiring Treatment | Time (in days) from transplant to the start date of the first dose of treatment for acute rejection. This includes acute rejection episodes requiring treatment that are not biopsy proven. | Transplantation through end of trial participation (up to 4.4 years post-transplant) | 
| Percent of Participants Requiring Anti-lymphocyte Therapy (OKT3, ATG) for an Acute Rejection Event | Anti-lymphocyte therapy is a drug that targets specific cells in the immune system called lymphocytes (white blood cells). This therapy helps stop the participant's immune system from attacking the donor kidney. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval. | Transplantation through end of trial participation (up to 4.4 years post-transplant) | 
| Number of Adverse Events, Including Number of Post-transplant Infections, Wound Complications, Lymphocoele, Post-transplant Diabetes Mellitus, and Malignancies | Adverse events that are reported as being a post-transplant infection, wound complication, lymphocoele (a collection of fluid in the lymphatic system), post-transplant diabetes mellitus or malignancy. | Transplantation through end of trial participation (up to 4.4 years post-transplant) | 
| Participant Renal Function as Measured by GFR Using CKD-EPI | Glomerular filtration rate (GFR) is a measure of kidney function and helps determine the stage of kidney disease. A value less than 15 indicates kidney failure, 15 to 29 indicates severe loss of kidney function, 30 to 44 indicates moderate to severe loss of kidney function, 45 to 59 mild to moderate loss of kidney function, 60 to 89 indicates mild loss of kidney function, and 90 or higher indicates normal kidney function. The equation developed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) is used to estimate GFR from serum creatinine. The value closest to and within 6 weeks of the day expected was selected. | 26, 52, 104, 156, and 208 Weeks Post-Transplant | 
| Participant Systolic Blood Pressure Over Time | Systolic blood pressure measures the pressure on the blood vessels when the heart is beats and thus is pushing blood to the rest of the body. A normal systolic blood pressure is lower than 120 mmHg. High blood pressure, as known as hypertension, is a risk factor for coronary artery disease, stroke, heart failure, and other complications if left unmanaged. The value closest to and within 6 weeks of the day expected was selected. | 26, 52, 104, 156, and 208 Weeks Post-Transplant | 
| Participant Diastolic Blood Pressure Over Time | Diastolic blood pressure measures the pressure in the arteries when the heart is at rest and is thus filled with blood. A normal diastolic blood pressure is lower than 80 mmHg. High blood pressure, as known as hypertension, is a risk factor for coronary artery disease, stroke, heart failure, and other complications if left unmanaged. The value closest to and within 6 weeks of the day expected was selected. | 26, 52, 104, 156, and 208 Weeks Post-Transplant | 
| Participant Total Cholesterol Over Time | Total cholesterol measures the amount of cholesterol found in the blood. Cholesterol is a waxy substance your body needs to build cells, but too much can be a problem since it can build-up in arteries. Narrowed arteries can result in heart attack or stroke. A value less than 200 mg/dL is considered good. The value closest to and within 12 weeks of the day expected was selected. | 26, 52, 104, 156, and 208 Weeks Post-Transplant | 
| Participant Glucose Level Over Time | This is a measure of glucose found in the blood. Glucose, a sugar, is an energy source that the body relies on to properly function. If levels are too high for a long period of time, diabetes can develop. Diabetes can result in many long-term complications such as eye, kidney, and nerve damage, stroke, and cardiovascular complications. Fasting levels for glucose should be around 70-99 mg/dL and less than 140 mg/dL within 2 hours after a meal. The value closest to and within 6 weeks of the day expected was selected. | 26, 52, 104, 156, and 208 Weeks Post-Transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney transplantation, Living donor transplant, Graft rejection, Graft loss, Induction with rituximab and ATG, Immunosuppression (IS)