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Health Condition(s) or Problem
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Kidney Transplantation; Graft Rejection; Immunosuppression
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Lay Summary
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Purpose of clinical trial; Evaluate the effectiveness of rituximab in C4d+ CAN
Primary objective; To determine whether anti-CD20 therapy can stabilize or improve renal
function and/or proteinuria in patients with C4d+, chronic (humoral) rejection in whom
standard therapeutic approaches have failed.
Secondary objective (s);
- To compare patient and graft survival between control and rituximab-treated groups
- To evaluate the adverse effect profile of rituximab in this group
- To correlate changes in circulating B cell numbers, anti-HLA and non-HLA Ab profiles
and titre with responses to standard therapy and / or rituximab
- To correlate changes in T cell responsiveness to alloantigens with responses to
standard therapy and / or rituximab
Study Design; Prospective, randomised, two arm, open-labeled
Study Endpoints; Primary
- Rate of deterioration in renal function, defined by slope of reciprocal creatinine
plot, on samples taken 3-5 months post-randomisation.
- Change in degree of proteinuria, where present, at 3-5 months post-randomisation 2°
endpoints, determined at 3-5 months post-randomisation and at 1, 2 and 3 years
post-recruitment are;
- Rate of deterioration in renal function, defined by slope of reciprocal creatinine
plot, determined by analysis of samples taken since previous assessment.
- Patient survival
- Graft survival
- Incidence of culture positive infection
- Incidence of malignancy
- Degree of proteinuria
- Changes in circulating CD20+ cells in peripheral blood
- Changes in anti-graft Ab titres, (measured every 3 months)
- Changes in T cell responsiveness to alloantigens (measured every 3 months).
Sample Size; 15 patients to be randomised to each arm (i.e. 30 patients randomised). Up to
120 patients will need to be enrolled into the study. In addition, in those participants
that received a living donor kidney, these donors will be approached to provide up to 5
samples of blood to help with the in vitro analyses.
Summary of eligibility criteria;
- Male or female renal allograft recipients 18-70 years of age
- more than 6/12 post-transplantation
- Either deteriorating allograft function on reciprocal creatinine plot or significant
proteinuria or both.
- C4d+ CAN on renal allograft biopsy
Investigational medicinal product and dosage; Rituximab, 1g on day 0 and 1g on day 14
Active comparator product(s); None
Route(s) of administration; Intravenous infusion
Maximum duration of treatment of a subject; 14 days with rituximab. The treatment arms of
the study, including optimisation period, formal run-in and post-randomisation phase lasts
for 10 months post-recruitment.
Procedures; Screening & enrollment. Potentially eligible patients will be identified by
screening renal allograft biopsies performed for 'creeping creatinine' and/or proteinuria.
Recruitment by informed consent prior to enrollment.
Procedures; Baseline. In addition to routine tests, blood for anti-HLA and non-HLA antibody
analysis and for peripheral blood mononuclear cell (PBMC) purification.
Procedures; Treatment period. 3 month run-in period on optimal conventional
immunosuppressive therapy, preceded by up to 2 months to allow tailored-optimization.
Patients will be reviewed at least six times in their normal transplant clinic appointments
for routine blood biochemistry, full blood count and urine analysis. At the end of the
run-in period, further blood will be taken for anti-graft antibody analysis and PBMC
purification. Those patients in whom allograft function stabilises and/or proteinuria
impr (from ClinicalTrials.gov)
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Who can enter the trial
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Inclusion Criteria:
- Functioning kidney allograft (with estimated (e) GFR by MDRD >20) and be >6/12
post-transplantation
- Deteriorating allograft function as defined by linear regression of reciprocal
creatinine plot. Deterioration will be defined as a negative slope over at least the
preceding 3 months (with at least 6 creatinines included) with an adjusted r2 >0.35
and a p value of =0.05 compared to horizontal baseline. Deterioration will be
confirmed by reduction in Cockcroft-Gault (CG) eGFR over the same period (to exclude
increases in body mass as a cause of a negative slope on reciprocal creatinine plots)
OR significant proteinuria as assessed by a urine protein/creatinine ratio of =50
- CAN, by Banff '97 criteria, and/or transplant glomerulopathy on renal allograft
biopsy performed within 6/12 of enrolment
- Diffuse, linear C4d deposition on at least 25% of peritubular capillary (PTC) and/or
glomerular EC of renal transplant biopsy when assessed by immunoperoxidase or >50% of
PTC (alone) when assessed by immunofluorescence
Exclusion Criteria:
- Ages below 18 years of age
- Suspicion of pregnancy confirmed by positive HCG pregnancy test
- Untreated ureteric obstruction on ultrasound of allograft
- History of acute allograft rejection in preceding 3/12
- History of MI in preceding 3/12
- History of malignancy in previous 5 years (excluding tumours limited to skin)
- Symptomatic IHD
- Recipient of simultaneous pancreas/kidney transplant
- Recipient of ABO-incompatible kidney
- Recipient who underwent an HLA desensitisation procedure prior to transplantation
- Evidence, on examination of renal allograft biopsy specimen, of recurrent or de-novo
disease (except IgA deposition in absence of mesangial proliferation)
- Evidence, on examination of renal allograft biopsy specimen, of CNI toxicity IF
ACCOMPANIED by mostly supra-therapeutic CNI trough levels in the 6 month period
preceding biopsy.
- Documented allergy to mouse or chimeric human/mouse proteins
- HepBsAg+, HepBcAb+, HCV Ab+ or HIV+.
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Who cannot enter the trial
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Inclusion Criteria:
- Functioning kidney allograft (with estimated (e) GFR by MDRD >20) and be >6/12
post-transplantation
- Deteriorating allograft function as defined by linear regression of reciprocal
creatinine plot. Deterioration will be defined as a negative slope over at least the
preceding 3 months (with at least 6 creatinines included) with an adjusted r2 >0.35
and a p value of =0.05 compared to horizontal baseline. Deterioration will be
confirmed by reduction in Cockcroft-Gault (CG) eGFR over the same period (to exclude
increases in body mass as a cause of a negative slope on reciprocal creatinine plots)
OR significant proteinuria as assessed by a urine protein/creatinine ratio of =50
- CAN, by Banff '97 criteria, and/or transplant glomerulopathy on renal allograft
biopsy performed within 6/12 of enrolment
- Diffuse, linear C4d deposition on at least 25% of peritubular capillary (PTC) and/or
glomerular EC of renal transplant biopsy when assessed by immunoperoxidase or >50% of
PTC (alone) when assessed by immunofluorescence
Exclusion Criteria:
- Ages below 18 years of age
- Suspicion of pregnancy confirmed by positive HCG pregnancy test
- Untreated ureteric obstruction on ultrasound of allograft
- History of acute allograft rejection in preceding 3/12
- History of MI in preceding 3/12
- History of malignancy in previous 5 years (excluding tumours limited to skin)
- Symptomatic IHD
- Recipient of simultaneous pancreas/kidney transplant
- Recipient of ABO-incompatible kidney
- Recipient who underwent an HLA desensitisation procedure prior to transplantation
- Evidence, on examination of renal allograft biopsy specimen, of recurrent or de-novo
disease (except IgA deposition in absence of mesangial proliferation)
- Evidence, on examination of renal allograft biopsy specimen, of CNI toxicity IF
ACCOMPANIED by mostly supra-therapeutic CNI trough levels in the 6 month period
preceding biopsy.
- Documented allergy to mouse or chimeric human/mouse proteins
- HepBsAg+, HepBcAb+, HCV Ab+ or HIV+.
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What will happen
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Drug; Rituximab; 2 doses of 1g 14 days apart; Rituximab; Mabthera; Other; Control arm; Continue of optimised oral immunosuppression; 2
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Primary aim
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Rate of deterioration in renal function, defined by slope of reciprocal creatinine plot; Change in degree of proteinuria, where present
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Secondary Aim
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Rate of deterioration in renal function, defined by slope of reciprocal creatinine plot, determined by analysis of samples taken since previous assessment; 1, 2 and 3 years post-recruitment; No; Patient survival; 5 months post-randomisation and at 1, 2 and 3 years post-recruitment; Yes; Graft survival; 5 months post-randomisation and at 1, 2 and 3 years post-recruitment; No; Incidence of culture positive infection; 5 months post-randomisation and at 1, 2 and 3 years post-recruitment; Yes; Incidence of malignancy; 5 months post-randomisation and at 1, 2 and 3 years post-recruitment; Yes; Degree of proteinuria; 1, 2 and 3 years post-recruitment; No; Changes in circulating CD20+ cells in peripheral blood; 5 months post-randomisation and at 1, 2 and 3 years post-recruitment; No; Changes in anti-graft Ab titres; 3 monthly to 3 years post-recruitment; No; Changes in T cell responsiveness to alloantigens; 3 monthly to 3 years post-recruitment; No
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Participant Information Sheet
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Sorry, not currently available
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Website
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Sorry, not currently available
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Recruitment Status
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Recruiting
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Nation
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England, Wales, Scotland
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Location
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Birmingham, Cambridge, Canterbury, Cardiff, Carshalton, Glasgow, Hull, Leeds, Bury St. Edmunds, London, Manchester
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