Combination Immunosuppressive Therapy to Prevent Kidney Transplant Rejection in Adults

Phase 1

Completed

Conditions: Kidney Transplantation
Kidney Disease

Interventions: Drug: Alemtuzumab
Drug: Sirolimus
Drug: Tacrolimus
Procedure: Kidney transplant
Drug: Methylprednisolone (or equivalent)
Drug: Acetaminophen
Drug: Diphenhydramine
Drug: Trimethoprim (TMP)/Sulfa (Bactrim, Septra)
Drug: Valgancyclovir
Drug: Acyclovir
Drug: Pentamidine
Drug: Clotrimazole
Drug: Nystatin

Registration Number: NCT00078559

Lead Sponsor: University of Wisconsin, Madison

Brief Summary: Transplant rejection occurs when a patient's body does not recognize the new organ and attacks it. Patients who have kidney transplants must take drugs to prevent transplant rejection. Alemtuzumab is a man-made antibody used to treat certain blood disorders. The purpose of this study is to test the safety and effectiveness of using alemtuzumab in combination with two other drugs, sirolimus and tacrolimus, to prevent organ rejection after kidney transplantation. This study will also test whether this combination of medications will allow patients to eventually stop taking antirejection medications entirely.

Study hypothesis: A new strategy of immunosuppression using alemtuzumab, tacrolimus, and sirolimus for human renal transplantation will permit a step-wise withdrawal from immunosuppressive drugs.

Detailed Description: Drugs that suppress the immune system, such as sirolimus and tacrolimus, have contributed to increased success of transplantation. However, to prevent organ rejection, transplant recipients need to take immunosuppressive drugs for the rest of their lives, and these drugs make patients more susceptible to infection, endangering their health and survival. Regimens that are less toxic to or can eventually be withdrawn from transplant recipients are needed. Alemtuzumab is a monoclonal antibody that binds to and depletes excess T cells in the bone marrow of leukemia patients. This study will determine the effects of intravenous alemtuzumab and oral sirolimus and tacrolimus after kidney transplantation. The study will also evaluate this regimen's potential to allow eventual discontinuation of components of long-term immunosuppressive therapy.

This study will last up to 4 years. Participants will undergo kidney transplantation on Day 0 and will receive intravenous doses of alemtuzumab, acetaminophen, and diphenhydramine on Days 0, 1, and 2, as well as methylprednisolone on Day 0. After transplant, patients will receive up to 10 days of valganciclovir or acyclovir. Participants will take tacrolimus daily by mouth for at least 60 days after transplant and sirolimus daily by mouth for at least 12 months after transplant. As part of opportunistic infection (OI) prophylaxis, participants will also take sulfamethoxazole-trimethoprim by mouth 3 times a week, valganciclovir or acyclovir for up to 10 days post-transplant, and clotrimazole or nystatin by mouth for at least 3 months post-transplant.

There will be a minimum of 62 study visits spread out over 4 years after transplant. Vital signs measurement, adverse event and OI reporting, medication history, physical exam, and blood collection will occur at selected visits. Sirolimus withdrawal will begin when a participant meets certain study criteria. The withdrawal process will occur over a minimum of 3 months at an approximate rate of 33% of the pre-withdrawal dose per month. Participants eligible for sirolimus withdrawal will undergo several kidney biopsies, including one 2 weeks prior to the start of withdrawal, 6 and 12 months after completion of withdrawal, 1 year after study enrollment, and annually thereafter.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 10

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Alemtuzumab	Methylprednisolone (or equivalent)	-
Alemtuzumab	Acyclovir	-
Alemtuzumab	Trimethoprim (TMP)/Sulfa (Bactrim, Septra)	-
Alemtuzumab	Kidney transplant	-
Alemtuzumab	Valgancyclovir	-
Alemtuzumab	Alemtuzumab	-
Alemtuzumab	Tacrolimus	-
Alemtuzumab	Sirolimus	-
Alemtuzumab	Acetaminophen	-
Alemtuzumab	Diphenhydramine	-
Alemtuzumab	Pentamidine	-
Alemtuzumab	Clotrimazole	-
Alemtuzumab	Nystatin	-

Primary Outcome Measures

Name	Time	Method
Number of Acute Rejections in All Enrolled Participants	Four years post-transplant	Number of acute rejections\[1\] in all enrolled subjects from the time of transplantation to the end of the trial (four years post-transplant) 1. Acute rejection is defined as a biopsy-proven rejection: a renal biopsy demonstrates acute cellular or humoral rejection of Banff\[2\] Grade 1B or greater; or presumed rejection in the absence of biopsy-proven rejection, the participant is treated for an unexplained 20% increase in serum creatinine. 2. Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999

Secondary Outcome Measures

Name	Time	Method
Number of Acute Rejections in All Enrolled Participants Following Sirolimus Withdrawal	Transplantation to end of study (up to four years post-transplant)	Following sirolimus withdrawal, the number of acute rejections\[1\] in all enrolled participants 1\] Acute rejection is defined as a biopsy-proven rejection: a renal biopsy demonstrates acute cellular or humoral rejection of Banff\[2\] Grade 1B or greater; or presumed rejection in the absence of biopsy-proven rejection, the participant is treated for an unexplained 20% increase in serum creatinine. \[2\] Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999
Number of Acute Rejections Between Initiation of Sirolimus Withdrawal and End of Study	Initiation of sirolimus to end of study (up to four years post-transplant)	Acute rejections\[1\] between initiation of sirolimus withdrawal and end of study 1\] Acute rejection is defined as a biopsy-proven rejection: a renal biopsy demonstrates acute cellular or humoral rejection of Banff\[2\] Grade 1B or greater; or presumed rejection in the absence of biopsy-proven rejection, the participant is treated for an unexplained 20% increase in serum creatinine. \[2\] Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999
Time From Transplantation to Acute Rejection in Participants for Whom Acute Rejection Occurred During the 1 Year Post-transplant Period	Transplantation to acute rejection (up to one year post-transplant)	Time (days) to acute rejection\[1\] for participants occurring during the year following transplantation 1\] Acute rejection is defined as a biopsy-proven rejection: a renal biopsy demonstrates acute cellular or humoral rejection of Banff\[2\] Grade 1B or greater; or presumed rejection in the absence of biopsy-proven rejection, the participant is treated for an unexplained 20% increase in serum creatinine. \[2\] Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999
Number of Deaths Stratified by Sirolimus Withdrawal Status	Transplantation to Death (up to four years post-transplant)	Participants who died during the study, all cause(s)
Time From Transplantation to Acute Rejection in Participants for Whom Sirolimus Withdrawal Was Not Initiated	Transplantation to acute rejection (up to four years post-transplantation)	Time (days) to acute rejection\[1\] for participants where sirolimus was not initiated 1\] Acute rejection is defined as a biopsy-proven rejection: a renal biopsy demonstrates acute cellular or humoral rejection of Banff\[2\] Grade 1B or greater; or presumed rejection in the absence of biopsy-proven rejection, the participant is treated for an unexplained 20% increase in serum creatinine. \[2\] Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999
Number of Participants Who Experienced Graft Loss Stratified by Sirolimus Withdrawal Status	Transplantation to Graft Loss (up to four years post-transplantation)	Participants who experienced graft loss\[1\] during study \[1\]Graft loss is defined as the institution of chronic dialysis (at least 6 consecutive weeks, excluding participants with delayed graft function), transplant nephrectomy, or retransplantation
Number of Severe Acute Rejections Stratified by Sirolimus Withdrawal Status	Transplantation to severe acute rejection (up to four years post-transplantation)	Participants who experienced severe acute rejections\[1\] during study 1. Severe acute rejection is defined as that which requires treatment with anti-lymphocyte antibody or is histologically evaluated as Type IIA or greater using the Banff 1997 criteria\[2\] 2. Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999
Number of Participants Requiring Anti-lymphocyte Therapy for an Acute Rejection, Stratified by Sirolimus Withdrawal Status	Transplantation to acute rejection (up to four years post-transplantation)	Participants who experienced acute rejection\[1\] during study which required anti-lymphocyte (OKT3, ATG) therapy 1\] Acute rejection is defined as a biopsy-prove rejection: a renal biopsy demonstrates acute cellular or humoral rejection of Banff\[2\] Grade 1B or greater; or presumed rejection in the absence of biopsy-proven rejection, the participant is treated for an unexplained 20% increase in serum creatinine. \[2\] Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999
Number of Alemtuzumab Associated Adverse Events, Stratified by Sirolimus Withdrawal Status	Transplantation to end of study (up to four years post-transplant)
Number of Tacrolimus Associated Adverse Events, Stratified by Sirolimus Withdrawal Status	Transplantation to end of study (up to four years post-transplant)
Number of Sirolimus Associated Adverse Events, Stratified by Sirolimus Withdrawal Status	Transplantation to end of study (up to four years post-transplant)
Number of Side Effects of Conventional Immunosuppression, Stratified by Withdrawal Status	Transplantation to end of study (up to four years post-transplant)	Side effects of conventional immunosuppression include increased body weight and hypertension
Change in Renal Function as Measured by Serum Creatinine, Stratified by Withdrawal Status	Transplantation to end of study (up to four years post-transplant)	Mean change from transplantation to Month 48 in serum creatinine. Normal serum creatinine range is from 0.7 - 1.4 mg/dL. In a transplant population, starting serum creatinine is higher than normal range. A negative change indicates better renal function