|- candidate number||2634|
|- NTR Number||NTR1000|
|- Date ISRCTN created||16-jul-2007|
|- date ISRCTN requested||9-jul-2007|
|- Date Registered NTR||19-jun-2007|
|- Secondary IDs|| |
|- Public Title||AMC-DRIP|
|- Scientific Title||Desensitization of highly pre-sensitized dialysis patients waiting for kidney transplantation by Rituximab, IVIG-L and rescue Plasmapheresis
|- ACRONYM||THE DRIP STUDY|
|- hypothesis||Donor-specific antibodies form a significant barrier in transplantation of highly pre-sensitized dialysis patients. Increased waiting time is associated with increased morbidity and mortality among these patients. Thus, there is a need to further develop desensitizing therapies not only to make transplantation for this group of patients feasible, but also to reduce the occurrence of acute and chronic antibody-mediated graft damage caused by HLA or non-HLA specific antibodies. Acute and chronic antibody-mediated graft damage is increasingly associated with decreased graft function and survival.|
|- Healt Condition(s) or Problem(s) studied||Renal transplant , Renal transplant recipients, Plasma renin activity (PRA) , Desensitization|
|- Inclusion criteria||Patients older than 18 years with end stage renal failure and a current PRA higher than 80 % who are for more than two years on the waiting list for a cadaveric donor kidney, and included in the AM program. Only heart beating donors will be accepted.|
|- Exclusion criteria||A. Complete IgA deficiency
C. History of anaphylaxis against blood/plasma products
D. Significant cardiac or pulmonary disease, hepatitis C or HIV infection, or malignancy
within the last 5 years
|- mec approval received||yes|
|- multicenter trial||yes|
|- planned startdate ||15-jul-2007|
|- planned closingdate||15-jan-2010|
|- Target number of participants||17|
|- Interventions||In vivo administration of Rituximab (two doses):
The first dose of Rituximab (MabThera, Roche) 375 mg/m2 will be administered intravenously five months prior to the transplantation. The second and last dose will be administered before transplantation and after the completion of a successful treatment course with 4 doses of monthly IVIG administrations. The changes in the acceptable mismatch antigens will be analyzed after each IVIG treatment course and the then extended profile of acceptable mismatches will be adjusted in the AM program. We expect that the patient can then be transplanted immediately or maximally up to 6 weeks thereafter.
Initial infusion: Start rate of 50 mg/hour; if there are no adverse side effects; increase the rate 50 mg/hour every 30 minutes, to a maximum of 400 mg/hour. Subsequent infusions: Start at 100 mg/hour; if it is safe; increase the rate 100 mg/hour every 30 minutes, to a maximum of 400 mg/hour. All recipients will be given acetaminophen (1000 mg) and Di-adresoneF (25 mg), tavegil (2 mg), 30 min before the infusion.
In vivo administration of IVIG:
Intravenous administration of IVIG (IVIG-L, Nanogam, Sanquin) in a dose of 2 g/kg with a maximum of 140 gram, in a dilute, low-osmolaric solution. IVIG-L administration will be started at a speed of 30 ml/hr during the first 15 minutes. IVIG-L can be infused with infusion rates up to 8 ml/min (7 ml/kg/hr) without occurrence of severe side effects (Sanquin Clinical Study Report KB 97003B). In case of minor side effects, infusion will be withhold and after full clinical recovery of symptoms restarted at 50% of the original speed. To avoid the risk of overhydration in dialysis patients, IVIG-L has to be given during dialysis in a 4-hr period and if necessary continued thereafter (dependent on the total dose which has to be infused), or otherwise IVIG-L infusion can be started on a not-dialysis day (dependent on the cardiovascular status of the patient and under clinical surveillance) followed by dialysis thereafter. No High Flux kidneys will be used in order to preserve and not to filter the administered IVIG.
Briefly, IVIG-L (2 g/kg; maximum dose: 140 g) will be administered, on dialysis or the day after, monthly maximally for 4 months with the last course one month before transplantation. If the patient who has completed the full desensitizing treatment course has to wait longer than 4 weeks on the AM list in order to find a cross match negative organ , then another IVIG-L dose should be administered. The number of IVIG-L infusions depends on the results of the in vitro tests (PRA and CMX against unacceptable antigens) after each dose.
If treatment consisting of the first dose of Rituximab and the full IVIG-L course of four monthly doses fail to achieve an acceptable low PRA and a negative CMX against the primarily unacceptable antigens, transplantation can not take place. In this case we will institute a ¡°rescue plasmapheresis¡± protocol encompassing maximal 7 courses of daily large volume pheresis (40 ml/kg body weight) substituting plasma with saline/albumin solution in order to remove the antibodies as it is known that a part of these patients can still respond to PP 5. If this occurs and the patient is eligible for transplantation, the second dose of Rituximab will be administered according to the protocol. After each third pheresis, plasma will be substituted with fresh frozen plasma (FFPs) in order to prevent and minimize the risk of bleeding.
|- Primary outcome||Primary end point is achievement of a negative cross-match test with the donor kidney and transplantability.|
|- Secondary outcome||Secondary objectives are
1. Patient and graft survival;
2. Graft function as assessed by calculated creatinine clearance, proteinuria, the number and severity of acute (antibody mediated) rejections, blood pressure (antihypertensive treatment), monitoring of infections and the occurrence of malignancies.|
|- Trial web site|
|- CONTACT FOR PUBLIC QUERIES||Dr. Ajda T. Rowshani|
|- CONTACT for SCIENTIFIC QUERIES||Dr. Ajda T. Rowshani|
|- Sponsor/Initiator ||Academic Medical Center (AMC), Department of Internal Medicine|
(Source(s) of Monetary or Material Support)
|Academic Medical Center (AMC), Department of Internal Medicine|
|- Publications||Not applicable.|
|- Brief summary||Rationale: Donor-specific antibodies form a significant barrier in transplantation of highly pre-sensitized dialysis patients. Increased waiting time is associated with increased morbidity and mortality among these patients. Thus, there is a need to further develop desensitizing therapies not only to make transplantation for this group of patients feasible, but also to reduce the occurrence of acute and chronic antibody-mediated graft damage caused by HLA or non-HLA specific antibodies. Acute and chronic antibody-mediated graft damage is increasingly associated with decreased graft function and survival.
Objective: Achievement of a negative Complement Dependent Cytotoxicity Cross Match Test (CMX) and transplantability
Study design: A prospective, open, observational multicenter clinical trail to evaluate the efficacy and tolerability of desensitizing therapy consisting of multiple high-dose intravenous immunoglobulins (IVIG-L, Nanogam, Sanquin), two doses of Rituximab (MabThera, Roche) and ¡±rescue¡± plasmapheresis in highly pre-sensitized dialysis patients.
Study population: Patients ¡İ 18 years old with end stage renal failure and a current Panel Reactivity Antibody level ¡İ 80 % who are for more than two years on the waiting list for a cadaveric donor kidney, and included in the Acceptable Mismatch (AM) Program.
Intervention: Pre treatment with Rituximab (MabThera, Roche, anti CD20 monoclonal antibody), intravenous immunoglobulins (IVIG-L, Nanogam, Sanquin)) and ¡±rescue¡± plasmapheresis. Desensitization will be instituted by the administration of Rituximab (one dose) 375 mg/m2 intravenously five months prior to the transplantation. A second and last dose will be administered before transplantation and after the completion of a successful treatment course with IVIG administrations. Four monthly doses of IVIG-L will be administered prior to the transplantation in a dose of 2 g/kg with a maximum of 140 gram which can be repeated monthly in case of prolonged waiting time for a matched donor kidney. If treatment consisting of the first dose of Rituximab and the full IVIG-L course fail to achieve an acceptable low PRA and a negative CMX against the primarily unacceptable antigens, the patients who show significant decrease of the PRA level (PRA¡Ü5%) will undergo ¡°rescue plasmapheresis¡±. This procedure encompasses maximal 7 courses of daily large volume pheresis (40 ml/kg body weight) substituting plasma with saline/albumin solution in order to remove the antibodies as it is known that a part of these patients can still respond to plasmapheresis and get transplanted afterwards.
Main study parameters/endpoints: Patients will be admitted each time for study interventions, i.e. intravenous administration of Rituximab, IVIG and also for plasmapheresis. To avoid the risk of overhydration, extra dialysis sessions will be planned dependent on the patient¡¯s clinical condition and the present residual renal function. During the admissions, physical examination and physician visits will take place on a daily base. Blood samples will be drawn to monitor the therapy and the possible side effects of medication.
|- Main changes (audit trail)|
|- RECORD||19-jun-2007 - 16-jul-2007|
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