Combination Immunosuppressive Therapy to Prevent Kidney Transplant Rejection in Adults

University of Wisconsin (UW)

Status and phase: Completed; Phase 2; Phase 1

Conditions: Kidney Transplantation; Kidney Disease

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

Study type: Interventional

Funder types: Other; NETWORK

Identifiers

NCT00078559

H-2003-0435 (Other Identifier)

DAIT ITN013ST

Details and patient eligibility

About

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.

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 Regimens that are less toxic to or can eventually be withdrawn from transplant recipients are needed.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

Enrollment: 10 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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10 participants in 1 patient group

Alemtuzumab

Experimental group

Treatment:

Drug: Nystatin

Procedure: Kidney transplant

Drug: Methylprednisolone (or equivalent)

Drug: Clotrimazole

Drug: Pentamidine

Drug: Sirolimus

Drug: Diphenhydramine

Drug: Tacrolimus

Drug: Acetaminophen

Drug: Valgancyclovir

Drug: Trimethoprim (TMP)/Sulfa (Bactrim, Septra)

Drug: Acyclovir

Drug: Alemtuzumab