Clinical trial NCT00078559: Combination Immunosuppressive Therapy to Prevent Kidney Transplant Rejection in Adults
Official title: The Use of Campath-1H, Tacrolimus, and Sirolimus Followed by Sirolimus Withdrawal in Renal Transplant Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Kidney Transplantation
Kidney Disease
Keywords: Immunosuppression
Renal Failure
Lead sponsor: University of Wisconsin, Madison
Sponsor class: OTHER
Collaborators: name: Immune Tolerance Network (ITN)
First posted: 2004-03-02
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 Regimens that are less toxic to or can eventually be withdrawn from transplant recipients are needed.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.

Eligibility criteria: Inclusion Criteria

* Kidney transplant with primary cadaveric or non-Human Leukocyte Antigen (HLA)-identical living donor kidney (0-3 HLA-antigen mismatch)
* Receiving only a kidney and no other organs
* Able to take medications by mouth
* Willing to use acceptable methods of contraception

Exclusion Criteria

* Received HLA-identical living-donor kidney transplant
* HLA-antigen mismatch greater than 3
* Panel reactive antibody (PRA) value greater than 10% at any time prior to enrollment
* Received a non-heart-beating donor allograft
* Received a kidney from a donor who is greater than 60 years of age
* End-stage Renal Disease (ESRD) due to Focal Segmental Glomulerosclerosis (FSGS)
* Previous kidney transplant
* Received multiorgan transplant
* Concomitant systemic corticosteroid therapy for other medical diseases
* Known hypersensitivity to alemtuzumab, tacrolimus, methylprednisolone, or sirolimus
* Human Immunodeficiency Virus (HIV) infected
* Hepatitis C virus infected
* Positive for hepatitis B surface antigen
* Received dual or en-bloc pediatric kidneys
* Anti-human Globulin (AHG) or T cell crossmatch positive
* Investigational drug within 6 weeks of study entry
* Known clinically significant cardiovascular or cerebrovascular disease
* Previous or current history of cancer or lymphoma. Patients with adequately treated basal or squamous cell skin carcinoma are not excluded.
* Clinically significant coagulopathy or a requirement for chronic anti-coagulation therapy precluding biopsy
* Cytomegalovirus (CMV)-negative recipient, if received kidney is from a CMV-positive donor
* History of a psychological illness or condition that, in the opinion of the investigator, may interfere with the study
* Graves disease. Patients who have been previously adequately treated with radioiodine ablative therapy are not excluded.
* Active systemic infections
* Platelets less than 100,000 cells/mm\^3 at study entry
* Pregnant or breastfeeding

Primary outcomes:
measure: Number of Acute Rejections in All Enrolled Participants
timeFrame: Four years post-transplant
Secondary outcomes:
measure: Number of Acute Rejections in All Enrolled Participants Following Sirolimus Withdrawal
timeFrame: Transplantation to end of study (up to four years post-transplant)
measure: Number of Acute Rejections Between Initiation of Sirolimus Withdrawal and End of Study
timeFrame: Initiation of sirolimus to end of study (up to four years post-transplant)
measure: Time From Transplantation to Acute Rejection in Participants for Whom Sirolimus Withdrawal Was Not Initiated
timeFrame: Transplantation to acute rejection (up to four years post-transplantation)
measure: Time From Transplantation to Acute Rejection in Participants for Whom Acute Rejection Occurred During the 1 Year Post-transplant Period
timeFrame: Transplantation to acute rejection (up to one year post-transplant)
measure: Number of Deaths Stratified by Sirolimus Withdrawal Status
timeFrame: Transplantation to Death (up to four years post-transplant)
measure: Number of Participants Who Experienced Graft Loss Stratified by Sirolimus Withdrawal Status
timeFrame: Transplantation to Graft Loss (up to four years post-transplantation)
measure: Number of Severe Acute Rejections Stratified by Sirolimus Withdrawal Status
timeFrame: Transplantation to severe acute rejection (up to four years post-transplantation)
measure: Number of Participants Requiring Anti-lymphocyte Therapy for an Acute Rejection, Stratified by Sirolimus Withdrawal Status
timeFrame: Transplantation to acute rejection (up to four years post-transplantation)
measure: Number of Alemtuzumab Associated Adverse Events, Stratified by Sirolimus Withdrawal Status
timeFrame: Transplantation to end of study (up to four years post-transplant)
measure: Number of Tacrolimus Associated Adverse Events, Stratified by Sirolimus Withdrawal Status
timeFrame: Transplantation to end of study (up to four years post-transplant)
measure: Number of Sirolimus Associated Adverse Events, Stratified by Sirolimus Withdrawal Status
timeFrame: Transplantation to end of study (up to four years post-transplant)
measure: Number of Side Effects of Conventional Immunosuppression, Stratified by Withdrawal Status
timeFrame: Transplantation to end of study (up to four years post-transplant)
measure: Change in Renal Function as Measured by Serum Creatinine, Stratified by Withdrawal Status
timeFrame: Transplantation to end of study (up to four years post-transplant)
Other outcomes:
Locations:
city: Madison
country: United States
facility: University of Wisconsin - Department of Medicine
state: Wisconsin
Study officials:
affiliation: Immune Tolerance Network (ITN)
name: A. D'jamali, MD, MS
role: PRINCIPAL_INVESTIGATOR
References:
citation: First MR. Tacrolimus based immunosuppression. J Nephrol. 2004 Nov-Dec;17 Suppl 8:S25-31.
citation: Gourishankar S, Turner P, Halloran P. New developments in immunosuppressive therapy in renal transplantation. Expert Opin Biol Ther. 2002 Jun;2(5):483-501. doi: 10.1517/14712598.2.5.483.
citation: Watson CJ, Bradley JA, Friend PJ, Firth J, Taylor CJ, Bradley JR, Smith KG, Thiru S, Jamieson NV, Hale G, Waldmann H, Calne R. Alemtuzumab (CAMPATH 1H) induction therapy in cadaveric kidney transplantation--efficacy and safety at five years. Am J Transplant. 2005 Jun;5(6):1347-53. doi: 10.1111/j.1600-6143.2005.00822.x.