Pancreas-Kidney Transplantation Clinical Trial
Official title:
An Open-label, Randomized, Prospective Study to Investigate the Safety and Efficacy of Campath-1H as an Induction Agent in Combination With Tacrolimus Monotherapy Compared to Short-course ATG-induction in Combination With Tacrolimus, Mycophenolate Mofetil and Short-term Steroids Application in de Novo SPK Transplanted Diabetic Patients
The purpose of this study is to determine and compare the efficacy of Campath-1H/Tacrolimus versus ATG/Tacrolimus/MMF therapy in conjunction with initial short-term steroids in Type 1-diabetic patients undergoing simultaneous pancreas-kidney allograft transplantation as well as to evaluate the safety of Campath-1H/Tacrolimus versus ATG/Tacrolimus/MMF in terms of drug-related complications and immunosuppression-associated complications.
Simultaneous pancreas-kidney (SPK) transplantation is a recommended treatment option for
type 1-diabetic patients suffering from end-stage kidney disease.1 Major factors
contributing to the success of SPK transplantation include improvements in surgical
technique and the provision of effective immunosuppressive strategies heralded by the
introduction of the calcineurin inhibitors.2 According to the International Pancreas
Transplant Registry (IPTR), since the mid-1990s, the most popular maintenance therapy has
been with Tacrolimus and Mycophenolate Mofetil (MMF), utilized in approximately 66% of SPK
transplanted recipients. Since 1994, the proportion of pancreas recipients who received
induction therapy has exceeded 70% and by that means induction therapy is used with greatest
frequency for pancreas recipients than for any other solid organ recipients. That is in
accordance with the registry analyses and the clinical trials listed below demonstrating the
highest graft survival rates for recipients given antibody induction therapy and maintained
on Tacrolimus.
A large European multicenter study compared the efficacy and safety of Tacrolimus versus the
microemulsion formulation of Cyclosporine in 205 SPK recipients. All of the patients
received additionally rabbit anti-T-cell induction therapy, MMF and short-term
corticosteroids. The study showed a significantly higher pancreas graft survival rate with
Tacrolimus (91%) than with Cyclosporine (74%; P<0.0005).3 A second US multicenter study
focused on the effect of antibody induction therapy in SPK recipients. The trial conducted
at 18 US pancreas transplant centers, randomized 87 recipients each to antibody induction
therapy versus no therapy. In the induction group, either T-cell depleting or nondepleting
antibodies were used. Maintenance therapy in both groups was Tacrolimus, MMF and steroids.
At 3 years, actual patient survival rates (94% vs. 90%) and pancreas graft survival rates
(76% vs. 76%) were similar between the two groups, but actual kidney survival rates were
significantly higher in the induction group (92% vs. 82%; P=0.04).4 A third US-Canadian
multicenter study assessed the safety and efficacy of two dosing regimens of daclizumab
versus no antibody induction in 185 SPK recipients maintained on Tacrolimus, MMF and
steroids. The probability of either kidney or pancreas rejection was lowest with two doses
of daclizumab (P=0.042). The authors concluded that daclizumab is effective in reducing the
incidence of acute rejection in SPK recipients, as compared with no antibody induction.5
During the past years increasingly more centers investigated the usage of Campath-1H
induction therapy in combination with the calcineurin inhibitors, MMF in the absence or with
a short course of steroids. A recent single-centre, retrospective study of SPK transplant
recipients involved two treatment arms with Campath (n=50) and Thymoglobuline (n=58). The
induction dose of Campath was 30mg and 6mg/kg for Thymoglobuline. Additionally all
recipients received a prednisone-free maintenance immunosuppressive regimen of Tacrolimus
and Sirolimus or MMF. The 3-year patient and graft survivals were excellent and similar
between the treatment arms. The mean creatinine value 1-year post-transplant was however
lower in the Campath subgroup (1.30 vs. 1.44 mg/dL). Furthermore advantages of Campath were
shown by a trend of decreased rates of CMV infection, PTLD and it was also less expensive.6
The purpose of a further study was to evaluate Campath-1H preconditioning and Tacrolimus
monotherapy in pancreas transplant recipients. Thirty-seven consecutive pancreas transplants
(20 SPK, 10 PAK and 7 PTA) were followed up for 7 months, utilizing 30mg Campath-1H
preconditioning. Two grams of intravenous methylprednisolone were administered, one prior to
starting the Campath-1H and another at reperfusion. Patient survival was 100%. Pancreas and
kidney graft survivals were 94% and 90%, respectively. Interestingly, all rejection episodes
were preceded by tacrolimus trough levels <9.0 ng/ml for an extended period of time, while
allograft rejection was not observed in pancreases or kidneys if the tacrolimus was >10
ng/ml. During the study period no infectious complications were seen. Although follow-up was
short, these results suggest that a regimen of Campath-1H induction and tacrolimus
monotherapy represents an effective immunosuppressive protocol for pancreas transplant
recipients.7
As demonstrated above, an increasing number of transplant centres have proposed to withdraw
or avoid steroids, nevertheless calcineurin inhibitors have remained the backbone of most
immunosuppressive protocols. The use of antibody induction therapy for pancreas transplant
recipients has been guided by practical experience, in the absence of randomised prospective
trials.8 A multicenter trial involving 130 kidney transplant recipients has started in our
center, investigating the safety and efficacy of Campath-1H in combination with Tacrolimus
monotherapy compared to a standard Tacrolimus/MMF/steroid regimen, demonstrating excellent
results with virtually no complications or side effects with Tacrolimus monotherapy after
Campath-1H induction. Based on the existing clinical trials and the experience of Campath-1H
therapy in our center we would like to investigate the long-term safety and efficacy of
Campath-1H induction and Tacrolimus monotherapy compared to a standard regimen with ATG
induction, Tacrolimus, MMF and short term steroids in a controlled, prospective, randomised
trial.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT02234349 -
Bile Acids and Incretins in Pancreas Kidney Transplant Patients
|
N/A | |
| Terminated |
NCT01280708 -
Protocol DIVAT-Uro
|