Clinical trial NCT00371904: Trial of Rituximab Given Pre-Transplant to Sensitised Live Donor Kidney Recipients
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Kidney Transplantation
Keywords: Rituximab
donor
sensitised
antibody
rejection
Lead sponsor: Hunter and New England Health
Sponsor class: OTHER
Collaborators: name: Melbourne Health
name: Princess Alexandra Hospital, Brisbane, Australia
name: Royal Prince Alfred Hospital, Sydney, Australia
name: Auckland City Hospital
name: Monash Medical Centre
name: Royal Perth Hospital
name: Westmead Hospital
name: Royal Adelaide Hospital
First posted: 2006-09-04
Enrollment: 192
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Biopsy proven antibody mediated rejection
timeFrame: 12 months
Secondary outcomes:
measure: Elimination of donor specific antibodies (DSA)
timeFrame: Day - 2 , 7; Months 1, 3, 6, 9 and 12
measure: C4d in biopsies
timeFrame: Day 7; Months 3 and 12
measure: Plasma exchanges
timeFrame: Month 12
measure: Death
timeFrame: Month 12
measure: Treated rejection
timeFrame: Month 12
measure: Graft loss
timeFrame: Months 3, 6 and 12
measure: Treatment failure
timeFrame: Months 6 and 12
measure: Calculation of glomerular filtration rate (GFR)
timeFrame: Months 1 - 12
measure: Slope of 1/serum creatinine (Ser. Cr)
timeFrame: Months 6 and 12
measure: 24-hour U protein
timeFrame: Months 3 and 12
measure: Safety
timeFrame: Month 12
measure: Cancer and infections
timeFrame: Month 12
Other outcomes:
Locations:
city: Newcastle
country: Australia
facility: Newcastle Transplant Unit, John Hunter Hospital
state: New South Wales
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
Study officials:
affiliation: Newcastle Transplant Unit, John Hunter Hospital
name: Paul R Trevillian, MBBS, FRACP
role: STUDY_CHAIR
affiliation: Melbourne Health
name: Solomon Cohney, MBBS, FRACP, PhD
role: STUDY_CHAIR
References: