Study of Rituximab to Treat Chronic Renal Transplant Rejection (RituxiCAN-C4)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by King's College London
Sponsor:
Collaborators:
Medical Research Council
Roche Pharma AG
Information provided by (Responsible Party):
A. Dorling, King's College London
ClinicalTrials.gov Identifier:
NCT00476164
First received: May 18, 2007
Last updated: April 22, 2014
Last verified: April 2014
  Purpose

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


Condition Intervention Phase
Kidney Transplantation
Graft Rejection
Immunosuppression
Drug: Rituximab
Other: Control arm
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomised Trial of Anti-Cd20 in C4d+ Chronic Allograft Nephropathy

Resource links provided by NLM:


Further study details as provided by King's College London:

Primary Outcome Measures:
  • Rate of deterioration in renal function, defined by slope of reciprocal creatinine plot [ Time Frame: 3-5 months post-randomisation ] [ Designated as safety issue: No ]
  • Change in degree of proteinuria, where present [ Time Frame: 3-5 months post-randomisation ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • Patient survival [ Time Frame: 5 months post-randomisation and at 1, 2 and 3 years post-recruitment ] [ Designated as safety issue: Yes ]
  • Graft survival [ Time Frame: 5 months post-randomisation and at 1, 2 and 3 years post-recruitment ] [ Designated as safety issue: No ]
  • Incidence of culture positive infection [ Time Frame: 5 months post-randomisation and at 1, 2 and 3 years post-recruitment ] [ Designated as safety issue: Yes ]
  • Incidence of malignancy [ Time Frame: 5 months post-randomisation and at 1, 2 and 3 years post-recruitment ] [ Designated as safety issue: Yes ]
  • Degree of proteinuria [ Time Frame: 1, 2 and 3 years post-recruitment ] [ Designated as safety issue: No ]
  • Changes in circulating CD20+ cells in peripheral blood [ Time Frame: 5 months post-randomisation and at 1, 2 and 3 years post-recruitment ] [ Designated as safety issue: No ]
  • Changes in anti-graft Ab titres [ Time Frame: 3 monthly to 3 years post-recruitment ] [ Designated as safety issue: No ]
  • Changes in T cell responsiveness to alloantigens [ Time Frame: 3 monthly to 3 years post-recruitment ] [ Designated as safety issue: No ]

Estimated Enrollment: 120
Study Start Date: January 2007
Estimated Study Completion Date: January 2018
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Rituximab
Infusion of 2 x 1g of rituximab, 14 days apart
Drug: Rituximab
2 doses of 1g 14 days apart
Other Name: Mabthera
Sham Comparator: 2 Other: Control arm
Continue of optimised oral immunosuppression

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 OR PTCitis OR glomerulitis with combined PTC/g score of ≥2.

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+.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00476164

Contacts
Contact: Anthony Dorling, PhD, FRCP +44 7188 5880 anthony.dorling@kcl.ac.uk
Contact: Thanuja Weerasinghe +447787996198 Thanuja.Weerasinghe@gstt.nhs.uk

Locations
United Kingdom
University Hospital Birmingham Recruiting
Birmingham, United Kingdom, B15 2LN
Contact: Simon Ball, MD FCRP         
Principal Investigator: Simon Ball, MD FRCP         
East Kent Hospitals University NHS Foundation Trust Not yet recruiting
Canterbury, United Kingdom, CT1 3NG
Contact: Michael Delaney, MRCP         
Principal Investigator: Michael Delaney, MRCP         
Univeristy Hospital of Wales Recruiting
Cardiff, United Kingdom, CF14 4XW
Principal Investigator: Sian Griffin, FRCP         
Epsom & St Helier University Hospitals Trust Not yet recruiting
Carshalton, United Kingdom, SM5 1AA
Contact: Mysore Phanish, MRCP         
Principal Investigator: Mysore Phanish, MRCP         
Western Infirmary Recruiting
Glasgow, United Kingdom, G11 6NT
Contact: Colin Geddes, FRCP         
Principal Investigator: Colin Geddes, FRCP         
Hull Royal Infirmary Recruiting
Hull, United Kingdom, HU3 2JZ
Principal Investigator: Sunil Bhandari, FRCP         
St Jame's University Hospital Recruiting
Leeds, United Kingdom, LS9 7TF
Principal Investigator: Richard Baker, PhD FRCP         
King's College London, Guy's Hospital Recruiting
London, United Kingdom, SE 19RT
Principal Investigator: Anthony Dorling, PhD FRCP         
Imperial College London and West London Renal & Transplantation Centre Recruiting
London, United Kingdom, W12 0NN
Principal Investigator: Adam McLean, DPhil FRCP         
The Royal Free Hospital Recruiting
London, United Kingdom, NW3 2PF
Principal Investigator: Peter Dupont, MRCP PhD         
Manchester Royal Infirmary Recruiting
Manchester, United Kingdom, M13 9WL
Principal Investigator: Michael Picton, FRCP         
Sponsors and Collaborators
King's College London
Medical Research Council
Roche Pharma AG
Investigators
Principal Investigator: Anthony Dorling, PhD FRCP King's College London
  More Information

No publications provided

Responsible Party: A. Dorling, Professor of Transplant Inflammation and Repair, King's College London
ClinicalTrials.gov Identifier: NCT00476164     History of Changes
Other Study ID Numbers: 2006-002330-38
Study First Received: May 18, 2007
Last Updated: April 22, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by King's College London:
chronic allograft nephropathy
C4d
Anti-CD20
B cells
Antibody

Additional relevant MeSH terms:
Rituximab
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents

ClinicalTrials.gov processed this record on October 01, 2014