Trial of Rituximab Given Pre-Transplant to Sensitised Live Donor Kidney Recipients (RAPTURE)

A Prospective Open Label Randomised Multicentre Study Evaluating the Efficacy & Safety of Rituximab Given Pre-Transplant to Sensitised Renal Allograft Recipients in Addition to a "Standard" Desensitisation Regimen Consisting of PE/IVIG & MMF

About one third of prospective kidney transplant recipients have antibodies in their blood directed against the tissues of their only available kidney donor. Recently, "desensitisation" treatments when administered pre-transplant have allowed successful transplantation of these patients despite high rates of acute antibody mediated rejection (AAMR). The investigators propose to test in a randomised controlled trial whether rituximab, a monoclonal antibody that depletes B-lymphocytes, will safely lower antibody mediated rejection (AMR) rates when added to "standard" therapy. The investigators will also test whether rituximab enables more patients to achieve a negative crossmatch against their donor and thereby allow more transplants to proceed.

Study Overview

• Status: Unknown
• Conditions: Kidney Transplantation
• Intervention / Treatment: Drug: Rituximab; Drug: Standard Care

Detailed Description

This study is designed to investigate in a prospective, randomised fashion whether a single intravenous dose of rituximab (375 mg/m2) given two weeks prior to transplant, in addition to standard therapy, will allow sensitised renal transplant subjects to achieve a negative CDC crossmatch and thereby proceed to live donor transplantation. We will also evaluate whether rituximab will reduce the number of AAMR episodes in the post-transplant period, compared to controls. All eligible subjects must have a positive T- and/or B-cell CDC or flow cytometry crossmatch and have donor-specific antibodies identified by solid-phase assay at screening. All subjects will receive a standard desensitisation regimen that includes plasma exchange/IVIG + MMF before and immediately after transplantation followed by a standard care immunosuppressive regimen (IL-2R antagonist, tacrolimus, mycophenolate mofetil [MMF] and corticosteroids) after transplantation.

• Study Type: Interventional
• Enrollment (Anticipated): 192
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Paul R Trevillian, MBBS, FRACP; Phone Number: +61414417311; Email: Paul.Trevillian@hnehealth.nsw.gov.au
• Study Contact Backup: Name: Solomon Cohney, MBBS, FRACP, PhD; Phone Number: +61393427159; Email: Solomon.Cohney@wh.org.au

Study Locations

• Australia
  • New South Wales
    • Newcastle, New South Wales, Australia, 2305
      • Recruiting
      • Newcastle Transplant Unit, John Hunter Hospital
      • Contact: Paul R Trevillian, MBBS, FRACP; Phone Number: +61249214326; Email: Paul.Trevillian@hnehealth.nsw.gov.au
      • Contact: Ann Stein, RN; Phone Number: +61249214341; Email: Ann.Stein@hnehealth.nsw.gov.au
      • Principal Investigator: Paul R Trevillian, MBBS, FRACP
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Not yet recruiting
      • Monash Medical Centre
      • Contact: John Kanellis, MBBS, PhD, FRACP; Phone Number: +61395943070; Email: john.kanellis@med.monash.edu.au
      • Contact: Janet Andrew; Phone Number: +61395943526; Email: j.andrew@southernhealth.org.au
      • Principal Investigator: John Kanellis, MBBS, PhD, FRACP
    • Parkville, Victoria, Australia, 3052
      • Not yet recruiting
      • Royal Melbourne Hospital
      • Contact: Shlomo Cohney, MBBS; Phone Number: +61393427159; Email: Solomon.Cohney@wh.org.au
      • Contact: Maria Farrell; Phone Number: +61393427077; Email: maria.farrell@mh.org.au
      • Principal Investigator: Shlomo Cohney, MBBS, PhD, FRACP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Subjects, age > 18 years
2. Subjects receiving a single organ renal transplant from a living donor
3. Positive T-cell and/or B-cell crossmatch by complement dependent cytotoxicity (CDC) and/or positive flow cytometry crossmatch with confirmed donor-specific antibodies on solid-phase assay at screening. Positive CDC T-cell and/or B-cell crossmatch titre must be less than or equal to 1:64.
4. Subjects capable of understanding the purposes and risks of the study and who can give written informed consent

Exclusion Criteria at Study Entry (4 weeks prior to transplant):

1. Primary renal transplant lost from acute rejection less than six months prior to randomisation
2. Women of childbearing potential with a positive serum or urine pregnancy test or nursing mothers
3. Subjects with history of malignancy (other than non melanoma skin cancer that has been totally excised with no recurrence for two years)
4. Subjects with known contraindications to treatment with rituximab
5. Subjects with haemoglobin < 8.5 g/dL, WBC value of < 3000/mm3 or a platelet count of < 50,000/mm3 that is unlikely to resolve prior to randomisation
6. Subjects with a positive ABO crossmatch with donor
7. Subjects with severe diarrhoea or other gastrointestinal disorders that might interfere with the ability to absorb oral medication and is unlikely to resolve prior to randomisation
8. Subjects participating in another interventional clinical trial or requiring treatment with un-marketed investigational drugs or who would be expected to require other medications prohibited by the protocol
9. Subjects who cannot be followed for the study duration
10. Subjects with disorders or conditions that may interfere with the ability to comply with study procedures and/or requirements

Additional Exclusion Criteria at Day -2 before Transplantation:

1. All exclusion criteria as at study entry
2. Positive T- and/or B-cell CDC crossmatch at Day -2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Drug: Rituximab; Single dose (375 mg/m2) of rituximab to be given intravenously (IV) 14 days prior to transplantation; Other Names: Mabthera
Active Comparator: 2	Drug: Standard Care; Standard care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Biopsy proven antibody mediated rejection	12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Elimination of donor specific antibodies (DSA)	Day - 2 , 7; Months 1, 3, 6, 9 and 12
C4d in biopsies	Day 7; Months 3 and 12
Plasma exchanges	Month 12
Death	Month 12
Treated rejection	Month 12
Graft loss	Months 3, 6 and 12
Treatment failure	Months 6 and 12
Calculation of glomerular filtration rate (GFR)	Months 1 - 12
Slope of 1/serum creatinine (Ser. Cr)	Months 6 and 12
24-hour U protein	Months 3 and 12
Safety	Month 12
Cancer and infections	Month 12

Collaborators and Investigators

• Sponsor: Hunter and New England Health
• Collaborators: Melbourne Health; Royal Prince Alfred Hospital, Sydney, Australia; Princess Alexandra Hospital, Brisbane, Australia; Royal Adelaide Hospital; Royal Perth Hospital; Auckland City Hospital; Monash Medical Centre; Westmead Hospital
• Investigators: Study Chair: Paul R Trevillian, MBBS, FRACP, Newcastle Transplant Unit, John Hunter Hospital; Study Chair: Solomon Cohney, MBBS, FRACP, PhD, Melbourne Health

Study record dates

Study Major Dates

• Study Start: April 1, 2006
• Study Completion (Anticipated): January 1, 2009

Study Registration Dates

• First Submitted: September 1, 2006
• First Submitted That Met QC Criteria: September 1, 2006
• First Posted (Estimate): September 4, 2006

Study Record Updates

• Last Update Posted (Estimate): May 21, 2008
• Last Update Submitted That Met QC Criteria: May 20, 2008
• Last Verified: May 1, 2008

More Information

Terms related to this study

• Keywords: Rituximab; antibody; rejection; donor; sensitised
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: RAPTURE