BK Viremia: Kinase Inhibition to Decrease Nephropathy Intervention Trial

INTERVENTION: Amended as of 17/08/2010: De novo transplant patients will have monthly measurements of urine or plasma BK virus at their centre. Once either urine or plasma is positive for BK, plasma will be sent to the central reference laboratory to measure BK by polymerase chain reaction. Patients with positive PCR for plasma BK (viremia) will be randomised to either standard therapy (control) or sirolimus/leflunomide (treatment). The control group (standard therapy: reduction of immunosuppression) will have the antimetabolite (mycophenolate mofetil, mycophenolate sodium or azathioprine) either discontinued or reduced at first occurrence of viremia. If the initial quantification of viremia is 10,000 copies or greater per ml of plasma, the antimetabolite will be discontinued. This level of viremia has been retrospectively associated with increased risk of BK nephropathy, and significant reduction of immunosuppression, such as complete withdrawal of one agent, is now accepted practice. Plasma quantitative PCR of less than 10,000 BK viral copies per ml will initially be treated with reduction of the dose of antimetabolite by 50%. This is consistent with the current practice of most Canadian centres. Plasma BK PCR will be performed monthly during the trial, and any quantitative value of greater than 10,000 copies per ml will lead to permanent discontinuation of the antimetabolite. If after one month the viremia has not reduced by 1 log unit, the calcineurin inhibitor will be reduced to target levels of 4‐8 ng/ml for tacrolimus, or 50‐100 ng/ml for cyclosporine. Patients will continue to be monitored for BK DNA in plasma. In the treatment arm (sirolimus and leflunomide), the calcineurin inhibitor will be discontinued, the antimetabolite will be discontinued, and the prednisone dose will be reduced to 5 mg per day. The patient will be treated with sirolimus, initially 4 mg per day, with dosage adjustment to attain trough levels of 6 ‐ 8 ng/ml. Leflunomide, the investigational pro CONDITION: BK nephropathy ; Urological and Genital Diseases ; Unspecified nephritic syndrome PRIMARY OUTCOME: Amended as of 17/08/2010:; Multiple failure times per subject will represent the primary study outcome. Failure events will be:; 1. Doubling of serum creatinine or an increase of at least 100 umol/L; 2. Need for renal replacement therapy for graft end‐stage failure; 3. Death; ; Binary change in serum creatinine will be defined as 100% increase (relative change) or 100 umol/L increase (absolute change) as compared to the lowest value between randomisation and the first 2 months; the change must persist for at least one month, with the event date being the initial assessment date. ; ; This multiple event approach is implied by design as patients may experience further events once the first has occurred. The likelihood of these further events may change after the first has occurred and as a result of BK infection providing clinical and biological support to the existence of correlation in the competing risks data arising from the present study. The competing risks of these further events may change as a result of treatment.; ; Initial information at time of registration:; Multiple failure times per subject will represent the primary study outcome. Failure events will be:; 1. Doubling of serum creatinine; 2. Need for renal replacement therapy for graft end‐stage failure, and ; 3. Death; ; This multiple event approach is implied by design as patients may experience further events once the first has occurred. The likelihood of these further events may change after the first has occurred and as a result of BK infection providing clinical and biological support to the existence of correlation in the competing risks data arising from the present study. The competing risks of these further events may change as a result of treatment. INCLUSION CRITERIA: Current inclusion criteria as of 01/02/2013: 1. All adults (aged greater than or equal to 18 years, either sex) de novo renal transplant patients with grafts from both living donors and deceased donors and up to two renal transplants prior to the current transplant 2. Presence of BK viremia based on a positive BK virus deoxyribonucleis acid polymerase chain reaction (DNA PCR) in plasma, of any degree 3. Greater than 1 month post‐kidney transplant 4. Provision of informed consent (self or legal representative) Previous INCLUSION CRITERIA: 1. All adults (aged greater than or equal to 18 years, either sex) de novo renal transplant patients with grafts from both living donors and deceased donors and up to two renal transplants prior to the current transplant 2. Presence of BK viremia based on a positive BK virus deoxyribonucleis acid polymerase chain reaction (DNA PCR) in plasma, of any degree 3. Greater than 2 months post‐kidney transplant

Epistemonikos ID: 4a9598ce513e20282b918f36fb2bb2c99359a0c4
First added on: Mar 20, 2020