Study of Alemtuzumab Versus Anti-thymocyte Globulin to Help Prevent Rejection in Kidney and Pancreas Transplantation

• ClinicalTrials.gov Identifier: NCT00331162
• Recruitment Status: Completed
• First Posted: May 29, 2006
• Results First Posted: June 6, 2018
• Last Update Posted: September 6, 2018
• Sponsor: Wake Forest University Health Sciences
• Information provided by (Responsible Party): Wake Forest University Health Sciences

Tracking Information

• First Submitted Date: May 26, 2006
• First Posted Date: May 29, 2006
• Results First Submitted Date: April 3, 2018
• Results First Posted Date: June 6, 2018
• Last Update Posted Date: September 6, 2018
• Actual Study Start Date: February 2005
• Actual Primary Completion Date: November 28, 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 3, 2018)

• Patient Survival [ Time Frame: 5 years ]
  The number of patients that survived after transplantation occurred was reported.
• Graft Survival [ Time Frame: 5 years ]
  The number of patients with graft survival after kidney alone, simultaneous pancreas-kidney (SPK), and pancreas after kidney (PAK) transplant.
• Acute Rejection [ Time Frame: 5 years ]
  The number of patients with acute rejection after transplantation was reported.

Original Primary Outcome Measures (submitted: May 26, 2006)

• Patient Survival
• Graft Survival
• Acute Rejection
• Hematologic adverse events
• Infectious adverse events
• Other adverse events
• Cost
• Health status and quality of life

Current Secondary Outcome Measures (submitted: May 3, 2018)

• Hematologic Adverse Events [ Time Frame: 2 years ]
• Infectious Adverse Events [ Time Frame: 2 years ]
  Number of events for infectious adverse events were reported (Polyoma virus nephropathy (PVD), cytomegalovirus (CMV), bacterial and fungal infections).
• Other Adverse Events [ Time Frame: 2 years ]
  Number of patients with other adverse events (posttransplant lymphoproliferative disorder (PTLD), and nonskin malignancy), were reported.
• Cost [ Time Frame: 2 years ]
• Health Status and Quality of Life [ Time Frame: 2 years ]

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Alemtuzumab Versus Anti-thymocyte Globulin to Help Prevent Rejection in Kidney and Pancreas Transplantation
• Official Title: Alemtuzumab Versus Thymoglobulin Induction Therapy in Kidney and Pancreas Transplantation
• Brief Summary: The purpose of this research study is to compare the effects of the two most commonly used anti-T cell induction agents(alemtuzumab and rabbit anti-thymocyte globulin) to prevent rejection in kidney and pancreas transplant patients. Alemtuzumab is Food and Drug Administration (FDA) approved for treating a certain type of cancer (leukemia), and Thymoglobulin® (rabbit anti-thymocyte globulin) is approved for anti-rejection treatment, but neither drug is FDA approved for administration at the time of transplantation to help prevent rejection. Even so, many transplant centers use these medications at the time of transplantation and believe that their use helps to decrease the risk of developing rejection following kidney and pancreas transplantation. Which drug might be better is not known. Subjects will receive either alemtuzumab (one administration) or rabbit anti-thymocyte (3 to 7 doses) at and within the first week of transplantation. Subjects will be assigned to either the alemtuzumab or rabbit anti-thymocyte globulin groups by chance. The two groups will be compared to see if there are meaningful differences for survival, organ function, side effects, and quality of life. The follow-up care after transplant for subjects in the study is the same as that for patients who are not in the study, except that a quality of life questionnaire (estimated to take 10 minutes to complete) will be completed at the time of transplant and through year 2 during selected scheduled clinic visits. A retrospective chart review will occur at 3-5 years post-transplant to follow incidence of chronic rejection, patient and graft survival and graft function.

Detailed Description

Anti-Thymocyte Globulin, rabbit (r-ATG, Thymoglobulin®) is a polyclonal antibody against T-lymphocytes that is used for the prevention and treatment of acute allograft rejection. r-ATG induction therapy is effective in preventing acute allograft rejection, however the usual 7-14 day course involves extensive clinical monitoring and is costly. Recent studies had suggested that smaller cumulative doses are efficacious for induction therapy, and may have an advantage by decreasing the adverse effects associated with the agent (such as leukopenia and thrombocytopenia). Our program subsequently modified our r-ATG induction regimen in November 2001 to give doses on alternate days for at least three doses and has achieved excellent results. However, this regimen is somewhat complex in that it requires central venous access for administration, pre-medication administration to prevent infusion-related reactions, and monitoring of vital signs during each infusion.

Alemtuzumab (Campath®) is a humanized monoclonal antibody to CD52 that is FDA approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), but has also been used for immunosuppression induction at the time of solid organ transplant and as anti-rejection therapy. CD52 is present on most lymphocytes, macrophages, monocytes, and NK cells, and causes antibody-dependent cell lysis following the binding of alemtuzumab to the CD52 surface antigen. Alemtuzumab produces significant lymphocyte depletion similar to r-ATG, so some investigators began evaluating it as a preconditioning agent in tolerance protocols (using very low-dose maintenance immunosuppression) in solid organ transplantation. While these studies showed no significant tolerogenic potential for alemtuzumab, one or two 20-30 mg doses of alemtuzumab produced a similar degree of lymphocyte depletion as r-ATG administration. Based on these preliminary data in transplant recipients and prior safety data obtained from safety and efficacy studies of alemtuzumab in patients with rheumatoid arthritis, some US transplant centers changed from using r-ATG to alemtuzumab as their primary induction agent. Most of these centers (notably Wisconsin and Northwestern, where more than 500 kidney and pancreas patients have received alemtuzumab, personal communication Dixon Kaufman, Northwestern) use one or two doses of alemtuzumab for induction, followed by a traditional 2-3 drug maintenance immunosuppressive regimen (rather than the low-dose immunosuppression used in the tolerance protocols).

Knechtle and colleagues from the University of Wisconsin have reported a comparable incidence of acute rejection and favorable graft survival in 130 patients who received a single intraoperative 30 mg dose (+/- an additional dose on post-operative day 1) of alemtuzumab compared with a historical cohort who received r-ATG, OKT3, an IL-2 receptor antagonist, or no induction. In addition, the group found that there was a dramatically lower incidence of acute rejection in the patients who experienced delayed graft function in the alemtuzumab group (9% vs 45% in the control group, p=0.0078).

The use of alemtuzumab as an induction agent in solid organ transplantation is appealing. Only a single intraoperative dose would be required (compared with between 2 and 6 additional doses of r-ATG post-op), thereby eliminating the necessity for central venous access and extensive clinical and nurse monitoring. In addition, the cost of therapy would be less with alemtuzumab than with r-ATG. At WFUBMC, 18 recipients of kidney or kidney/pancreas transplants who received alemtuzumab have had only a 9% six-month rejection rate. Our clinical experience suggests that the agents produce similar results; however, a prospective, randomized study to compare the safety and efficacy of alemtuzumab with r-ATG has not been reported. Also, although alemtuzumab would offer a significant medication cost savings over r-ATG, the impact on the overall cost of care has yet to be established. A comparative study will help us decide if we should make alemtuzumab our new standard of care at this institution.

The purpose of this study is to evaluate the use of alemtuzumab (Campath-1H) for induction therapy in kidney and pancreas transplantation compared to our standard of care, alternate-day r-ATG.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention
• Condition: Graft Rejection

Intervention

• Drug: Alemtuzumab
  30 mg/100ml NS intraoperatively. Start after dexamethasone administration and prior to reperfusion of the allograft. Infuse over a minimum of 2 hours.
• Drug: Anti-Thymocyte Globulin

  1.5 mg/kg per dose through a central line intraoperatively and on POD# 2 and 4, then continue on alternate days until a therapeutic tacrolimus(or cyclosporine) level is achieved, or until the SCr < 3-4 mg/dL.

  Give first dose over 6 hours, subsequent doses over 4 hours.

  Premedication to be given with the first 3 doses:

  Tylenol 650mg PO/PR Benadryl 25-50mg PO/IV Daily scheduled corticosteroid dose or other corticosteroid as deemed appropriate.

  Hold infusion if temperature > 100.5ºF; Adjust dose for low WBC or Plt count Peripheral Thymoglobulin administration: Prepare dose in 500cc NS; Add heparin 1,000 units and hydrocortisone 20mg to the bag; Infuse over a minimum of 6 hours

Study Arms

• Active Comparator: 1
  Alemtuzumab
  Intervention: Drug: Alemtuzumab
• Active Comparator: 2
  Anti-Thymocyte Globulin
  Intervention: Drug: Anti-Thymocyte Globulin

Publications *

• Brennan DC, Flavin K, Lowell JA, Howard TK, Shenoy S, Burgess S, Dolan S, Kano JM, Mahon M, Schnitzler MA, Woodward R, Irish W, Singer GG. A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. Transplantation. 1999 Apr 15;67(7):1011-8. Erratum in: Transplantation 1999 May 27;67(10):1386.
• Knechtle SJ, Pirsch JD, H Fechner J Jr, Becker BN, Friedl A, Colvin RB, Lebeck LK, Chin LT, Becker YT, Odorico JS, D'Alessandro AM, Kalayoglu M, Hamawy MM, Hu H, Bloom DD, Sollinger HW. Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. Am J Transplant. 2003 Jun;3(6):722-30.
• Kaufman DB, Leventhal JR, Gallon LG, Parker MA. Alemtuzumab induction and prednisone-free maintenance immunotherapy in simultaneous pancreas-kidney transplantation comparison with rabbit antithymocyte globulin induction - long-term results. Am J Transplant. 2006 Feb;6(2):331-9.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 3, 2018): 222
• Original Enrollment (submitted: May 26, 2006): 100
• Actual Study Completion Date: November 28, 2011
• Actual Primary Completion Date: November 28, 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

Enrollment of kidney transplant patients has been completed. The protocol has been amended to enroll 50 additional subjects who will receive either a simultaneous pancreas and kidney transplant, pancreas after kidney transplant, or solitary pancreas transplant.

Inclusion Criteria:

• Male or female patients who receive a simultaneous pancreas and kidney transplant, pancreas after kidney transplant, or solitary pancreas transplant
• Age 18 to 65
• Females of child bearing potential must have a negative pregnancy test at time of transplant
• Ability to give informed consent

Exclusion Criteria:

• Inability to give informed consent
• ABO incompatibility
• T-cell or B-cell positive cross match
• Patients with a previous hypersensitivity to alemtuzumab, anti-thymocyte globulin, or any monoclonal or polyclonal antibody preparation
• Current active infection (currently receiving antibiotics, treatment for active infection within 1 week of transplant, or medical judgement)
• Hepatitis B surface antigen positive
• Human immunodeficiency virus positive
• Any malignancy within 2 years except for successfully treated basal or squamous cell carcinoma of skin
• Pregnancy
• Breast feeding women

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00331162
• Other Study ID Numbers: BG04-498
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Wake Forest University Health Sciences
• Study Sponsor: Wake Forest University Health Sciences
• Collaborators: Not Provided

Investigators

• Principal Investigator: Alan C Farney, MD, Ph.D.; Wake Forest University Health Sciences

• PRS Account: Wake Forest University Health Sciences
• Verification Date: August 2018