Study of Rituximab to Treat Chronic Renal Transplant Rejection (RituxiCAN-C4)
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 improves will have normal transplant clinic follow-up appointments and have blood taken for further anti-graft antibody and PBMC purification up to every 3 months for 3 years. Those with continued deterioration in either allograft function or persisting or worsening proteinuria will be randomised. These patients will be reviewed during their normal transplant clinic appointments until the primary end-point and will need to have at least 6 routine blood biochemistry, full blood count and urine analysis during the final 3 months of this period, post-randomisation. At the primary end-point, further blood will be taken for anti-graft antibody analysis and PBMC.
Procedures; End of Study. •Follow up will continue for 3 years, with blood taken for anti-graft antibody analysis and PBMC purification every three months
Procedures for safety monitoring during trial; Regular patient interviews and examination, routine haematological and biochemical analyses. Serious adverse events will be reported and forwarded to the sponsor, MHRA, LREC and Roche as appropriate The WLRATC transplant research committee will discuss the trial and any safety concerns at their regular three monthly meetings. Data will be reviewed after 30 and also after 60 people have been enrolled.
Criteria for withdrawal of patients on safety grounds; Serious adverse effects related to rituximab infusion
Other: Control arm
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Randomised Trial of Anti-Cd20 in C4d+ Chronic Allograft Nephropathy|
- Rate of deterioration in renal function, defined by slope of reciprocal creatinine plot [ Time Frame: 3-5 months post-randomisation ]
- Change in degree of proteinuria, where present [ Time Frame: 3-5 months post-randomisation ]
- Rate of deterioration in renal function, defined by slope of reciprocal creatinine plot, determined by analysis of samples taken since previous assessment [ Time Frame: 1, 2 and 3 years post-recruitment ]
- Patient survival [ Time Frame: 5 months post-randomisation and at 1, 2 and 3 years post-recruitment ]
- Graft survival [ Time Frame: 5 months post-randomisation and at 1, 2 and 3 years post-recruitment ]
- Incidence of culture positive infection [ Time Frame: 5 months post-randomisation and at 1, 2 and 3 years post-recruitment ]
- Incidence of malignancy [ Time Frame: 5 months post-randomisation and at 1, 2 and 3 years post-recruitment ]
- Degree of proteinuria [ Time Frame: 1, 2 and 3 years post-recruitment ]
- Changes in circulating CD20+ cells in peripheral blood [ Time Frame: 5 months post-randomisation and at 1, 2 and 3 years post-recruitment ]
- Changes in anti-graft Ab titres [ Time Frame: 3 monthly to 3 years post-recruitment ]
- Changes in T cell responsiveness to alloantigens [ Time Frame: 3 monthly to 3 years post-recruitment ]
|Study Start Date:||January 2007|
|Estimated Study Completion Date:||April 2017|
|Primary Completion Date:||May 2015 (Final data collection date for primary outcome measure)|
Infusion of 2 x 1g of rituximab, 14 days apart
2 doses of 1g 14 days apart
Other Name: Mabthera
|Sham Comparator: 2||
Other: Control arm
Continue of optimised oral immunosuppression
Please refer to this study by its ClinicalTrials.gov identifier: NCT00476164
|University Hospital Birmingham|
|Birmingham, United Kingdom, B15 2LN|
|East Kent Hospitals University NHS Foundation Trust|
|Canterbury, United Kingdom, CT1 3NG|
|Univeristy Hospital of Wales|
|Cardiff, United Kingdom, CF14 4XW|
|Epsom & St Helier University Hospitals Trust|
|Carshalton, United Kingdom, SM5 1AA|
|Glasgow, United Kingdom, G11 6NT|
|Hull Royal Infirmary|
|Hull, United Kingdom, HU3 2JZ|
|St Jame's University Hospital|
|Leeds, United Kingdom, LS9 7TF|
|The Royal Free Hospital|
|London, United Kingdom, NW3 2PF|
|King's College London, Guy's Hospital|
|London, United Kingdom, SE 19RT|
|Imperial College London and West London Renal & Transplantation Centre|
|London, United Kingdom, W12 0NN|
|Manchester Royal Infirmary|
|Manchester, United Kingdom, M13 9WL|
|Principal Investigator:||Anthony Dorling, PhD FRCP||King's College London|