The aim of this trial is to compare the safety and efficacy of a single dose of
Thymoglobulin, rabbit derived antithymocyte globulin (Thymoglobulin, SangStat, Fremont, CA)
to our standard four dose, four day Thymoglobulin induction regimen from the time of
transplantation through a six month follow-up period. The primary endpoint will be the
incidence of acute rejection. Secondary endpoints will include serious adverse events,
evaluation of renal function, patient and graft survival, incidence of infectious
complications, incidence of post-transplantation lymphoproliferative disorder (PTLD),
duration and extent of lymphocyte depletion and immunoassays for evidence of recipient immune
response to the allograft as well as duration of hospital stay.
Induction therapy, using polyclonal or monoclonal antibody preparations as an adjunct
immunosuppressive agent during the initial transplant period, has helped to decrease the
incidence of acute rejection significantly. In the 1980â€™s acute rejection occurred in
approximately 50% of renal transplant recipients. In the current era of transplantation, the
combination of potent induction agents and newly available maintenance immunosuppressive
agents has reduced the acute rejection rate to less than 20% at most transplant centers. Our
center has routinely achieved acute rejection rates of approximately 5% using a standard
induction protocol with the polyclonal antibody agent Thymoglobulin.
Preventing acute rejection significantly decreases the requirement for re-hospitalization,
the need for diagnostic renal allograft biopsy and subsequent exposure to high dose
corticosteroids and other immunosuppressive agents. The threat of early allograft loss
secondary to rejection refractory to treatment or permanent injury and shortened graft
survival following treatment of a severe rejection is also circumvented.
Polyclonal antibody preparations are produced by immunizing animals with human lymphocytes or
thymocytes. Polyclonal antibody preparations are approved for treatment of acute renal
allograft rejection, but are routinely used as induction agents and for prevention of
rejection in all solid organ allografts. Commercially available preparations in the United
States are equine/thymocyte derived (Atgam, Pharmacia & Upjohn, Kalamazoo, MI) and
rabbit/thymocyte derived (Thymoglobulin, Genzyme, Cambridge, MA).
Rabbit derived preparations are thought to be potentially more efficacious than equine
derived products. Studies performed at this renal transplant center demonstrated that
Thymoglobulin has superior efficacy compared to Atgam in the prevention of rejection (1). Not
only was the acute rejection rate lower, but graft survival was also better at 1 and 5-years
(1). [Hardinger, 2004 #18]. This result has been attributed in part to a more pronounced and
prolonged lymphopenia induced by Thymoglobulin (2).
The broad specificity of polyclonal agents to multiple cell signaling and adhesion molecules
provides a theoretic advantage compared to monoclonal antibodies. In addition to inducing a
profound and prolonged lymphopenia through complement-dependent lysis or by opsonization and
phagocytosis, the broad specificity of polyclonal antibody agents affects multiple
costimulatory and adhesion molecules involved in cellular and antibody mediated immune
processes. The effects on adhesion molecules, cytokines, chemokines and platelets may be
critical to the noted decrease in the incidence of delayed renal allograft function
associated with initiation of Thymoglobulin therapy intraoperatively (3). Prevention of
delayed graft function may also subsequently decrease the incidence of acute rejection and
prolong allograft survival.
The use of a potent induction agent such as Thymoglobulin also allows for a delayed
introduction of maintenance immunosuppression with calcineurin inhibitors in the immediate
post-transplant setting. The ability to delay the introduction of therapeutic doses of
calcineurin inhibitors, when necessary, can also assist in decreasing the incidence of
delayed graft function and simplifies patient management in this time period.
Thymoglobulin has now become the preferred polyclonal agent used for induction in renal
transplantation. The most recent complete yearly data from the Scientific Registry of
Transplant Recipients in 2003 indicated that 70% of all renal transplant recipients in that
calendar year received some form of induction therapy. Thymoglobulin (34% of patients) was
the most commonly administered agent, while one of two available monoclonal antibody
preparations directed against the interleukin-2 receptor (IL2-R) was administered to
approximately 35% of renal transplant recipients (4).
When Thymoglobulin is used in the treatment of acute rejection, a total dose of 10-12mg/kg is
often administered over the course of several days (5). The optimal dose of Thymoglobulin
that should be administered for induction is unclear, although a primate model suggests a
total human equivalent dose of approximately 6mg/kg may be appropriate (6). Most transplant
centers using Thymoglobulin for induction have administered a total dose of 6-10mg/kg, given
at varying intervals (usually daily or every other day) with each individual dose usually
given as 1 to 1.5mg/kg/day over approximately six hours. Our standard induction protocol has
been 1.5mg/kg/day for a total of four doses (total dose 6mg/kg).
The ability to administer Thymoglobulin as a single, large dose has several potential
pharmacoeconomic benefits. This administration protocol would simplify post-transplant care
in the hospital and allow for earlier patient discharge. Cost savings would result from both
a shorter hospital stay and decreased administration costs associated with fewer intravenous
The administration of a single, large dose infusion of Thymoglobulin has been used in an
attempt to induce â€œpropeÂ´â€ (Latin for almost) allograft tolerance (7). In this study, that
included 50 renal allograft recipients, a single dose infusion of Thymoglobulin (5mg/kg) was
used in conjunction with a marked minimization of maintenance immunosuppression. The
induction protocol was well tolerated, and maintenance immunosuppression consisted of
monotherapy with tacrolimus.
Another study described the administration of Thymoglobulin 5mg/kg/day given as two separate
doses (10mg/kg total) in 39 renal allograft recipients (8). One dose was administered on the
day of transplantation and the subsequent dose on post-transplant day number one. No patients
in this study were withdrawn secondary to adverse events and the acute rejection rate was 6%
with a patient and graft survival of 95% at a mean follow-up of 14.5 months.
We have previously performed a short course Thymoglobulin induction study using an initial
dose of 3mg/kg with subsequent doses of 1.5mg/kg on post-transplant days one and two (9).
This regimen was well tolerated and resulted in a low acute rejection rate of 5%, a one year
graft survival of 95% and earlier hospital discharge compared to a previously standard seven
day Thymoglobulin induction protocol.
Thus, we hypothesize that a single dose of Thymoglobulin (6mg/kg), initiated intraoperatively
and administered over the course of 24 hours, will have comparable safety and efficacy as
compared to our current standard induction protocol of four separate doses of Thymoglobulin
1.5mg/kg (total dose 6mg/kg). Single dose administration of Thymoglobulin should provide a
low rate of acute rejection, a low rate of delayed graft function, allow for delayed
introduction of calcineurin inhibitors if indicated, and potentially allow for earlier
patient discharge while consuming fewer resources. If this single dose induction protocol
demonstrates similar safety and efficacy to our current standard four dose induction
protocol, it may become our standard of care. This study may also be a bridge to subsequent
dose finding studies for single dose Thymoglobulin administration and subsequent comparative
studies of single-dose Thymoglobulin to other induction agents.
1. Brennan DC, Flavin K, Lowell JA, et al. A randomized, double-blinded comparison of
Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal
transplant recipients. Transplantation 1999;67(7):1011-1018.
2. Hardinger KL, Schnitzler MA, Miller B, et al. Five-year follow up of thymoglobulin
versus ATGAM induction in adult renal transplantation. Transplantation
3. Goggins WC, Pascual MA, Powelson JA, et al. A prospective, randomized, clinical trial of
intraoperative versus postoperative Thymoglobulin in adult cadaveric renal transplant
recipients. Transplantation 2003;76(5):798-802.
4. Shapiro R, Young JB, Milford EL, et al. Immunosuppression: evolution in practice and
trends, 1993-2003. Am J Transplant 2005;5(4 Pt 2):874-886.
5. Gaber AO, First MR, Tesi RJ, et al. Results of the double-blind, randomized,
multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of
acute graft rejection episodes after renal transplantation. Transplantation
6. Preville X, Flacher M, LeMauff B, et al. Mechanisms involved in antithymocyte globulin
immunosuppressive activity in a nonhuman primate model. Transplantation
7. Starzl TE, Murase N, Abu-Elmagd K, et al. Tolerogenic immunosuppression for organ
transplantation. Lancet 2003;361(9368):1502-1510.
8. Uslu A, Nart A, Coker I, et al. Two-day induction with thymoglobulin in kidney
transplantation: risks and benefits. Transplant Proc 2004;36(1):76-79.
9. Agha IA, Rueda J, Alvarez A, et al. Short course induction immunosuppression with
thymoglobulin for renal transplant recipients. Transplantation 2002;73(3):473-475.
|Condition or disease
|First Submitted Date||October 06, 2005|
|Last Update Posted Date||October 13, 2006|
|Start Date||January 01, 2006|
|Completion Date||February 01, 2006|
|Primary Completion Date||N/A|
|Results First Submitted Date||N/A|
|Received Results Disposit Date||N/A|
Current Primary Outcome Measures
Incidence of acute rejection.
Original Primary Outcome Measures
Current Secondary Outcome Measures
Serious adverse events
patient and graft survival
duration and extent of lymphocyte depletion and immunoassays for evidence of recipient immune response
duration of hospital stay
Original Secondary Outcome Measures
|Brief Title||Single Dose Thymoglobulin for Induction in Adult Renal Allograft Recipients|
|Official Title||Non-Phased Study of the Use of a Single Dose of Thymoglobulin for Immunosuppressive Induction in Renal Transplant Recipients as Compared to a Standard Four Dose Regimen|
|Target Follow-Up Duration|| N/A|
|Completion Date||February 01, 2006|
1. Patients 18 years of age or older
2. All consenting adult renal transplant recipients scheduled to receive induction
therapy (deceased donor, living-related, or living-unrelated)
3. Females of childbearing age must have a negative pregnancy test performed at the time
of admission for transplantation
4. Patient or guardian agrees to participate in the study and signs the informed consent.
5. No known contraindication to the administration of Thymoglobulin
1. A known allergy to rabbit proteins or previous significant intolerance of
2. Pregnant women or nursing mothers
3. Patients with serological evidence of infection with HIV-1, human T-cell leukemia
virus type 1 (HTLV-1), or the presence of serum hepatitis B surface antigen (HBsAg)
4. Recipients of a human leukocyte antigen (HLA) identical living donor renal allograft
5. Recipients of simultaneous multiple organ transplantation
6. Recipients with a pre-existing, non-renal, solid organ transplant
7. Recipients of â‰¥2 previous renal allografts
8. Patients with a history of malignancy with evidence of recurrence within 2 years
(except adequately treated localized squamous or basal cell carcinoma of the skin).
9. Any patient who, in the opinion of the investigator, has a significant medical or
psychosocial problem that should preclude them from the study.
|Age||18 Years to N/A|
|Accepts Healthy Volunteers||No|
|Listed Location Countries
|Other Study ID Numbers
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
|IPD Sharing Statement
Matthew J Koch, MD
Washington University School of Medicine