Combination Immunosuppressive Therapy to Prevent Kidney Transplant Rejection in Adults
Condition: Kidney Transplantation; Kidney Disease
MeSH terms: Kidney Diseases
Study type: Interventional
Phase: Phase 1/Phase 2

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      that are less toxic to or can eventually be withdrawn from transplant recipients are needed.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

Intervention name(s): Alemtuzumab; Sirolimus; Tacrolimus; Kidney transplant; Methylprednisolone (or equivalent); Acetaminophen; Diphenhydramine; Trimethoprim (TMP)/Sulfa (Bactrim, Septra); Valgancyclovir; Acyclovir; Pentamidine; Clotrimazole; Nystatin
Intervention type(s): Drug; Drug; Drug; Procedure; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): 30mg intravenous infusion on days 0 (transplant), 1, and 2; 2mg/day orally within 24-48 hrs post-transplant, and adjusted to achieve blood levels of 8-12 ng/mL for 1 year; 2mg orally twice daily, on days 1-60; Kidney transplant with primary cadaveric or non-HLA-identical living donor kidney (0-3 HLA-antigen mismatch); 250 mg intravenous infusion 60 minutes prior to first dose of alemtuzumab; 650 mg may be given 30-60 minutes prior to start of each infusion of alemtuzumab to prevent infusion related side effects such as fever, skin rash and pruritis; 25 mg may be given 30-60 minutes prior to start of each infusion of alemtuzumab to prevent infusion related side effects such as fever, skin rash and pruritis; 1 double strength tablet 3 times a week from day 1 through 1 year post-transplant.; Given orally beginning on day 1 for up to 10 days post-transplant (until participant discharged from hospital if prior to 10 days). Dose adjusted based on participants calculated creatinine clearance; 400 mg orally twice daily or 800 mg orally four times daily (dose adjusted based on calculated creatinine clearance and cytomegalovirus antibody serologic status of donor and recipient) for a minimum of 3 months starting when valganciclovir discontinued.; 300 mg/6 mL inhalation therapy once monthly for a total of 6 treatments. First treatment given within one week post-transplant for participants with a known allergy or intolerance to sulfa; 10 mg orally four times daily for a minimum of 3 months post-transplant (subjects take either clotrimazole or nystatin, not both); 500,000 units/5 mL orally four times daily for a minimum of 3 months post-transplant (subjects take either nystatin or clotrimazole, not both)
Intervention MeSH terms: Acetaminophen; Diphenhydramine; Promethazine; Sirolimus; Trimethoprim, Sulfamethoxazole Drug Combination; Nystatin; Clotrimazole; Miconazole; Pentamidine; Trimethoprim; Acyclovir; Valganciclovir; Methylprednisolone; Alemtuzumab; Tacrolimus
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Immunosuppression; Renal Failure