BK virus (BKV) is a member of the polyomavirus family with a prevalence of up to 90% in the general population. In immunocompromized individuals, such as kidney transplant recipients (KTRs) who receive immunosuppressant therapy to prevent graft rejection, BKV turns into an opportunistic pathogen. BK viremia has been reported to occur in 10-30% of KTRs. BKV is recognized as a leading cause of impaired graft function and premature transplant loss, and is therefore a serious condition in kidney transplant patients. At present, there are no effective agents specifically against BKV available and thus no standard treatment that can effectively reduce or prevent BKV infection/reactivation after renal transplantation. Therefore, the proposed indication for the AntiBKV neutralizing antibody is the treatment of BK virus infections and prevention of BK virus associated complications in KTRs. This study has been designed to evaluate the safety, tolerability, and pharmacokinetic of ascending doses of AntiBKV, a fully human highly neutralising antibody against BKV, administered as a single or multiple intravenous infusions to healthy adult participants. The data obtained in this study will provide the basis for further clinical development of AntiBKV.
BK virus (BKV) is a member of the polyomavirus family with a prevalence of up to 90% in the general population. It lies dormant and rarely causes disease in healthy individuals. However, in immunocompromized individuals, such as kidney transplant recipients (KTRs) who receive immunosuppressant therapy to prevent graft rejection, BKV turns into an opportunistic pathogen. BKV replication can be detected before the development of BK virus associated nephropathy (BKVAN) and first virus shedding is detected in the urine. BK viremia has been reported to occur in 10-30% of KTRs. BKVAN progression is detected by a median of 8 weeks after establishment of the persistent viremia, and occurs most commonly in the first 2 years post-transplantation or following treatment of graft rejection. BKV infection/reactivation in these patients can lead to progression to BKVAN in up to 10% of all KTRs, while ultimately leading to graft dysfunction in 38% of patients and loss in 20% of patients presenting with BK viremia. BKV is recognized as a leading cause of impaired graft function and premature transplant loss, and is therefore a serious condition in kidney transplant patients. At present, there are no effective agents specifically against BKV available and thus no standard treatment that can effectively reduce or prevent BKV infection/reactivation after renal transplantation. The current standard of care after kidney transplantation involves prospective screening for BKV reactivation post-transplantation and subsequent reduction of immunosuppression to strengthen immune responses against BKV. Although reduction of immune suppression is a widely accepted management option, approaches for dose tapering differ with no consensus existing regarding when and which agent should be reduced or stopped following a diagnosis of BKV infection. The proposed indication for the AntiBKV neutralizing antibody is the treatment of BK virus infections and prevention of BK virus associated complications in KTRs. In KTRs, the detection of the BK virus in the blood has been found to be strongly associated with the development of BKVAN and the grade of BK viremia correlates with the onset of the renal disease. A decrease of the virus load significantly reduces the chance for progression to BKVAN. Treatment of BK viremia with AntiBKV in KTRs with BKV infection/reactivation would allow for continued optimal immunosuppression to prevent graft rejection in these patients. This study is the first clinical study to be conducted with AntiBKV and has been designed to evaluate the safety, tolerability, and pharmacokinetic of ascending doses of AntiBKV administered as single or multiple intravenous infusions to healthy adult participants. The data obtained in this study will provide the basis for further clinical development of AntiBKV.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
SINGLE
Enrollment
40
CMAX Clinical Research Pty Ltd
Adelaide, South Australia, Australia
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
To assess the number of participants with treatment related adverse events following a single ascending doses (Part 1) and multiple ascending doses (Part 2) of AntiBKV administered intravenously to healthy adult participants.
Time frame: Screening (Day -1) to final visit post-treatment (Day 113) for Part 1 and final visit post-treatment (Day 197) for Part 2.
Change in blood haematology values
To evaluate the safety and tolerability of single ascending doses (Part 1) and multiple ascending doses (Part 2) of AntiBKV administered intravenously to healthy adult participants. Haematology data will be summarised for each scheduled visit, including observed values, change from baseline, number of out-of-range values and number of clinically significant values.
Time frame: Screening (Day -1) to final visit post-treatment (Day 113) for Part 1 and final visit post-treatment (Day 197) for Part 2.
Change in blood biochemistry values
To evaluate the safety and tolerability of single ascending doses (Part 1) and multiple ascending doses (Part 2) of AntiBKV administered intravenously to healthy adult participants. Biochemistry data will be summarised for each scheduled visit, including observed values, change from baseline, number of out-of-range values and number of clinically significant values.
Time frame: Screening (Day -1) to final visit post-treatment (Day 113) for Part 1 and final visit post-treatment (Day 197) for Part 2.
Change in urinalysis values
To evaluate the safety and tolerability of single ascending doses (Part 1) and multiple ascending doses (Part 2) of AntiBKV administered intravenously to healthy adult participants. Urinalysis data will be summarised for each scheduled visit, including observed values, change from baseline, number of out-of-range values and number of clinically significant values.
Time frame: Screening (Day -1) to final visit post-treatment (Day 113) for Part 1 and final visit post-treatment (Day 197) for Part 2.
Change in blood pressure
To evaluate the safety and tolerability of single ascending doses (Part 1) and multiple ascending doses (Part 2) of AntiBKV administered intravenously to healthy adult participants. Blood pressure results will be summarized for each scheduled timepoint, including observed values, change from baseline, number of out-of-range values and number of clinically significant values.
Time frame: Screening (Day -1) to final visit post-treatment (Day 113) for Part 1 and final visit post-treatment (Day 197) for Part 2.
Change in heart rate
To evaluate the safety and tolerability of single ascending doses (Part 1) and multiple ascending doses (Part 2) of AntiBKV administered intravenously to healthy adult participants. Heart rate will be summarized for each scheduled timepoint, including observed values, change from baseline, number of out-of-range values and number of clinically significant values.
Time frame: Screening (Day -1) to final visit post-treatment (Day 113) for Part 1 and final visit post-treatment (Day 197) for Part 2.
Change in respiratory rate
To evaluate the safety and tolerability of single ascending doses (Part 1) and multiple ascending doses (Part 2) of AntiBKV administered intravenously to healthy adult participants. Respiration rate will be summarized for each scheduled timepoint, including observed values, change from baseline, number of out-of-range values and number of clinically significant values.
Time frame: Screening (Day -1) to final visit post-treatment (Day 113) for Part 1 and final visit post-treatment (Day 197) for Part 2.
Change in body temperature
To evaluate the safety and tolerability of single ascending doses (Part 1) and multiple ascending doses (Part 2) of AntiBKV administered intravenously to healthy adult participants. Body temperature will be summarized for each scheduled timepoint, including observed values, change from baseline, number of out-of-range values and number of clinically significant values.
Time frame: Screening (Day -1) to final visit post-treatment (Day 113) for Part 1 and final visit post-treatment (Day 197) for Part 2.
Participants with abnormal physical examination findings.
To evaluate the safety and tolerability of single ascending doses (Part 1) and multiple ascending doses (Part 2) of AntiBKV administered intravenously to healthy adult participants. Abnormal physical examination findings during scheduled physical exams will be listed.
Time frame: Screening (Day -1) to final visit post-treatment (Day 113) for Part 1 and final visit post-treatment (Day 197) for Part 2.
Change in P wave duration in electrocardiogram measurement
To evaluate the safety and tolerability of single ascending doses (Part 1) and multiple ascending doses (Part 2) of AntiBKV administered intravenously to healthy adult participants. ECG parameters will be descriptively summarized for each scheduled timepoint, including observed values and change from baseline.
Time frame: Screening (Day -1) to final visit post-treatment (Day 113) for Part 1 and final visit post-treatment (Day 197) for Part 2.
Change in PR interval in electrocardiogram measurement
To evaluate the safety and tolerability of single ascending doses (Part 1) and multiple ascending doses (Part 2) of AntiBKV administered intravenously to healthy adult participants. ECG parameters will be descriptively summarized for each scheduled timepoint, including observed values and change from baseline.
Time frame: Screening (Day -1) to final visit post-treatment (Day 113) for Part 1 and final visit post-treatment (Day 197) for Part 2.
Change in QRS duration in electrocardiogram measurement
To evaluate the safety and tolerability of single ascending doses (Part 1) and multiple ascending doses (Part 2) of AntiBKV administered intravenously to healthy adult participants. ECG parameters will be descriptively summarized for each scheduled timepoint, including observed values and change from baseline.
Time frame: Screening (Day -1) to final visit post-treatment (Day 113) for Part 1 and final visit post-treatment (Day 197) for Part 2.
Pharmacokinetics measured by the maximum plasma concentration (Cmax)
To assess the pharmacokinetic profile of AntiBKV in healthy participants after single (Part 1 and first dose in Part 2) or multiple (Part 2) intravenous dose administration.
Time frame: Treatment Day 1 to final visit (Day 113) for Part 1 and final visit (Day 197) for Part 2.
Pharmacokinetics measured by the time of Cmax (Tmax)
To assess the pharmacokinetic profile of AntiBKV in healthy participants after single (Part 1 and first dose in Part 2) or multiple (Part 2) intravenous dose administration.
Time frame: Treatment Day 1 to final visit (Day 113) for Part 1 and final visit (Day 197) for Part 2.
Pharmacokinetics measured by the area under the curve (AUC)
To assess the pharmacokinetic profile of AntiBKV in healthy participants after single (Part 1 and first dose in Part 2) or multiple (Part 2) intravenous dose administration.
Time frame: Treatment Day 1 to final visit (Day 113) for Part 1 and final visit (Day 197) for Part 2.
Pharmacokinetics measured by the terminal elimination rate constant (λz)
To assess the pharmacokinetic profile of AntiBKV in healthy participants after single (Part 1 and first dose in Part 2) or multiple (Part 2) intravenous dose administration.
Time frame: Treatment Day 1 to final visit (Day 113) for Part 1 and final visit (Day 197) for Part 2.
Pharmacokinetics measured by the half life
To assess the pharmacokinetic profile of AntiBKV in healthy participants after single (Part 1 and first dose in Part 2) or multiple (Part 2) intravenous dose administration.
Time frame: Treatment Day 1 to final visit (Day 113) for Part 1 and final visit (Day 197) for Part 2.
Immunogenicity measured by anti-drug antibody (ADA) production
Samples will be tested for the presence of ADAs. ADA titers and the presence of neutralizing antibodies will be determined for ADA positive samples
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Time frame: Treatment Day 1 to final visit (Day 113) for Part 1 and final visit (Day 197) for Part 2.