Safety and Efficacy of Alemtuzumab in Pediatric Intestinal Transplantation
Condition: Evidence of Liver Transplantation; Rejection; ALEMTUZUMAB
Study type: Interventional
Phase: Phase 2

Summary: 
      This open-label clinical trial will evaluate the safety and efficacy of Alemtuzumab (Campath,
      Bayer Corp., Pittsburgh) in children (0-17) and adults (18-25) receiving intestinal
      transplant. Seventy-five subjects receiving primary or repeat intestine transplantation will
      be enrolled. Primary endpoints include the incidence and severity of biopsy-proven acute
      cellular rejection, the incidence of freedom from steroids at 5 years, and the incidence of
      subjects with steroid-free Tacrolimus at whole blood concentrations < 10 ng/ml. Secondary
      endpoints include a) incidence and severity of opportunistic infections (CMV and EBV),
      post-transplant lymphoproliferative disorder (PTLD), and chronic rejection b) use of
      non-immunosuppressive co-medications, c) time to repopulation of all lymphocyte subsets, d)
      longitudinal characterization of donor-specific alloreactivity in mixed lymphocyte responses
      (MLR), to identify the time at which it decreases to a level less than third-party-specific
      alloreactivity e) longitudinal expression (mRNA) of genes, to identify rejection- and
      non-rejection-specific genes and f) characterization of whole genome mutations, which show
      differences in parent-to-child transmission between rejectors and non-rejectors. This will
      identify rejection- and non-rejection-specific genes bearing genetic variants, which might
      impact on gene function, and complement candidate gene identification efforts based on SNP
      transmission.
    

Detailed description: 
      Intraoperatively, it is our impression that Alemtuzumab may predispose to mild coagulopathy.
      Therefore, we have elected to administer steroids, and withhold Alemtuzumab in the operating
      room for all small bowel transplant recipients.

        1. Premedication with acetaminophen 10 mg/kg orally + diphenhydramine 1 mg/kg intravenously
           + methylprednisolone 2 mg/kg, intravenously will occur 30 minutes before Alemtuzumab
           administration.

        2. Steroids up to 10 mg/kg as bolus will be administered intravenously in the operating
           room prior to reperfusion of the allograft followed by decreasing amounts of low-dose
           steroids post-transplant.

           Day 1 post-transplant: up to 5 mg/kg can be given Day 2 post-transplant: up to 4 mg/kg
           can be given Day 3 post-transplant: up to 3 mg/kg can be given Day 4 post-transplant: up
           to 2 mg/kg can be given Day 5 post-transplant: up to 1 mg/kg can be given

           Maintenance steroids are tapered thereafter by switching to equivalent amounts of oral
           prednisone, as soon as ileus results and oral intake intake is possible. By the end of
           the first month, all patients receive no more than 2.5-5 mg/day of prednisone. This
           amount is exceeded only if rejection occurs. Long-term prednisone usage may be elected
           in patients re-transplanted for chronic rejection.

        3. A single dose of Alemtuzumab 0.4-0.5 mg/kg will be given intravenously slowly
           post-operatively. Total dose will not exceed 30 mg.

      Procedures:

        1. Tacrolimus will be initiated at 0.01 mg per kg body weight orally. If biopsy-proven
           rejection does not occur, Tacrolimus will be titrated to whole blood concentrations:

           Month 1: 15-20 ng/ml Months 2-3: 10-15 ng/ml Month 4-6: 8-10 ng/ml Months 6-12: 5-10
           ng/ml

        2. This minimization protocol will be delayed by 3 months if biopsy proven acute cellular
           rejection occurs. At the event of rejection, Tacrolimus minimization and steroids
           sparing will be discontinued and standard immunosuppression will be instituted. For
           example, if rejection occurs, Tacrolimus is increased to month 1 levels of 15-20 ng/ml,
           and steroids added to the regimen. Steroids will be reduced or eliminated within 3
           months of rejection, and tacrolimus minimization resumed as described above. These
           levels of Tacrolimus are our standards of care in the event of rejection. Current
           immunosuppressive protocols at our center include rabbit anti-human thymocyte globulin
           (rATG) with Tacrolimus monotherapy, or Tacrolimus + steroid without induction.

        3. Laboratory tests per clinical protocol. The clinical standard of care will be followed
           in performing post-Tx monitoring labs consisting of complete blood count with
           differential count, serum sodium, potassium, chloride, bicarbonate, BUN, creatinine and
           glucose, and liver function tests consisting of Total bilirubin, aspartate alanine
           transaminase (ALT), aspartate glutamine transaminase (AST), and glutamyl galactosyl
           transaminase (GGT), and TAC whole blood concentrations. These laboratory tests are
           performed at least weekly in the first and second months, twice monthly in month 3, and
           monthly thereafter to the sixth month. The extra 1 to 11 ml needed for pharmacodynamic
           and pharmacogenomic studies is discussed further in items 5 and in Table 1.

        4. Surveillance intestinal allograft biopsies will be performed per clinical surveillance
           protocol-twice weekly in the first month, weekly in the second month, two-weekly in the
           third month, and at least monthly thereafter until the end of the 6th month, and at
           least annually thereafter. Surveillance biopsies are done because no blood test exists
           to indicate intestinal allograft dysfunction.
    

Intervention name(s): Alemtuzumab
Intervention type(s): Drug
Intervention description(s): Alemtuzumab is a monoclonal antibody directed against the CD52 antigen. A single dose of 0.3-0.4 mg/kg is given to enrolled subjects at the time of intestine transplantation, 30 minutes after premedication with acetaminophen, diphenhydramine and methylprednisolone
Other intervention name(s): Campath H-1 (Genzyme, Cambridge, MA)
Intervention MeSH terms: Alemtuzumab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Rejection