Safety, Tolerability and Efficacy of AntiBKV as Treatment of BKV Infection in Kidney Transplant Recipients

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, and efficacy of AntiBKV in reducing BKV DNAemia and progression to biopsy-confirmed BKVAN in Kidney Transplant Recipients (KTRs). The study includes two parts. The phase II part will evaluate the safety of AntiBKV in KTRs and establish proof of concept. The phase III part will assess the efficacy of AntiBKV in KTRs. For both the phase II and phase III parts, participants will be randomized to receive either four doses of AntiBKV or four doses of placebo (every 4 weeks). Both the phase II and phase III parts will follow identical study assessments and schedules for participants. Based on an interim analysis after phase II total sample size for the trial will be defined. Eligible participants will receive an intravenous infusion of the investigational medicinal product (IMP) that will be administered four times at a 4-week interval. Seven days following the first IMP administration, participants will be re-evaluated for BKV DNAemia and, if appropriate, changes of immunosuppressive treatment will be started. After administration of the final dose, participants will return as out participants for periodic safety, BKV DNAemia, and PK follow-up assessments until the end of the trial visits, 26 weeks post last IMP application. Regular kidney biopsies will be performed at baseline (prior to infusion) and on Day 141 (8 weeks after full dosing). An additional biopsy will be taken on Day 267 (optional) and as clinically indicated.

Official Title
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Safety, Tolerability and Efficacy of AntiBKV as Treatment of BKV Infection in Kidney Transplant Recipients, a Randomized Phase II/III Study, Double-blind and Placebo-controlled

Conditions
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BK Viremia; BKV DNAemia

Intervention / Treatment
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* Biological: Anti-BK polyomavirus (AntiBKV)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged 18 years or older Kidney transplantation within 24 months prior to enrollment Kidney transplant recipient with first-time BKV DNAemia (evaluated during routine clinical monitoring by the local laboratory and acknowledged by a physician within 4 months prior to Day 1). BKV DNAemia is either defined by BKV-DNAemia of one time >10,000 copies/mL, or >1,000 copies/mL sustained for at least one week (confirmed by 2 consecutive measurements. Note: The second, most recent laboratory value must be acknowledged by a physician within 4 months prior to Day 1) Kidney transplant recipients with adequate and/or stable allograft function as indicated by estimated glomerular filtration rate ((e)GFR) ≥ 30 mL/min Female subjects (if of childbearing potential) must agree to use adequate and reliable contraceptive measures throughout their participation in the trial. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies Ability to provide written informed consent Exclusion Criteria: Patients with previous diagnosis of BK viremia (defined as one time >10,000 copies/mL, or >1,000 copies/mL sustained for at least one week (confirmed by 2 consecutive measurements) since last kidney transplant Known hypersensitivity to any component of the investigational medicinal product (IMP) Transplanted kidney disease with an estimated glomerular filtration rate ((e)GFR) < 30 mL/minute at screening Uncontrolled acute or chronic infection other than BK virus (BKV) infection at screening which might interfere with study participation at the discretion of the investigator Recipients who are treated or planned to be treated with a mammalian Target of Rapamycin (mTOR) inhibitor or belatacept as part of their immunosuppression regimen post-transplantation at the time of enrollment and during the study period. Recipients who are treated or planned to be treated during study participation with leflunomide at the time of enrollment and during the study period. Recipients who in the opinion of the investigator are likely to require antibody-depletion therapy during trial participation. Antibody-depleting therapies include but are not necessarily limited to plasmapheresis, immunoadsorption, and intravenous immunoglobulins (IVIg) Recipients with active kidney transplant rejection or focal segmental glomerulosclerosis (FSGS) shown by renal biopsy Recipients who have medical conditions or receive concomitant medications that prevent the recipient from undergoing allograft biopsy Recipients with known donor-specific antibodies (DSA) (de novo or pre-transplantation). Kidney transplant recipients with low-level pretransplant DSAs (<1000 mean fluorescence intensity (MFI) can be includred if no impact on the study assessments is expected by the discretion of the investigator Recipients with extremely high BK virus (BKV)-DNAemia (>10,000,000 copies/mL) or hemorrhagic cystitis Recipients who in the opinion of the investigator are likely to develop recurrent native kidney disease (e.g. immunoglobulin A [IgA] nephritis, focal segmental glomerulosclerosis [FSGS], C3 glomerulonephritis) Recipients with a functionally significant ureteral stricture Pregnant or nursing (lactating) women Known current active or latent TB or any history, in the opinion of the investigator, that confers a risk of reactivation of latent TB and precludes the use of conventional immunosuppression History of splenectomy or asplenia Any condition, that in the opinion of the investigator, would interfere with the evaluation of the investigational product or interpretation of the participant safety data or study results History of malignancy within the past 5 years, except completely excised basal cell or squamous cell carcinoma of the skin, or cervical carcinoma in situ at least 2 years prior to screening Participation in another interventional clinical trial during trial participation or within 30 days prior to the investigational medicinal product (IMP) dosing or planned dosing History of alcoholism or drug addiction within 1 year of screening. Substance use disorder will be an exclusion criterion, at investigator's discretion

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel assignment Randomized
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anti-BK polyomavirus (AntiBKV)<br>1,000mg Anti-BK polyomavirus (AntiBKV) intravenous infusion every 4 weeks (4 doses) | Biological: Anti-BK polyomavirus (AntiBKV)<br>* Participants in the study arm will each receive 4 doses (1,000 mg) administered at 4 weekly intervals administered on Days 1, 29, 57 and 85.<br>|
| Placebo Comparator: Placebo<br>Placebo intravenous infusion every 4 weeks (4 doses) | Biological: Anti-BK polyomavirus (AntiBKV)<br>* Participants in the study arm will each receive 4 doses (1,000 mg) administered at 4 weekly intervals administered on Days 1, 29, 57 and 85.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants without detectable BK virus in the blood at Day 141 | To evaluate the therapeutic efficacy of AntiBKV in decreasing BK virus plasma concentration below the detection limit at Day 141 in Kidney Transplant Recipients (KTRs) with BKV DNAemia and to assess the sample size for the phase III part of the study. | At day 141 | 
| To assess whether treatment with AntiBKV decreases BK virus plasma concentration below the detection limit at day 141 in Kidney Transplant Recipients (KRTs) with BKV DNAemia. | Proportion of participants without detectable BK virus in the blood at day 141 | At day 141 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess whether treatment with AntiBKV decreases viral DNA load throughout the study in Kidney Transplant Recipients (KTRs) with BKV DNAemia in a clinically relevant manner. | The proportion of participants with at least -1 log10 IU/mL change from baseline in BK viral DNA load up to day 267. | Baseline and up to day 267 | 
| Incidence, severity, and causal relationship of treatment-emergent adverse events (TEAEs) according to treatment group throughout the study | Blood samples for safety laboratory assessments (Standard measures for hematology and chemistry) will be taken at all visits. Monitoring for injection site reactions and infusion-related reactions will be conducted as part of routine safety assessments for this study, including signs and symptoms of anaphylaxis - performed at every visit, during infusion and for at least 1 hour after infusion. Vital signs will be taken at every visit and monitored every 30 minutes after start of infusion until at least 1 hour after end of infusion. | Screening visit up to day 267 (+/- 14 days) | 
| Assess whether treatment with AntiBKV results in a clinically relevant decrease in viral DNA load in Kidney Transplant Recipients (KTRs) with BKV DNAemia throughout the study | Percentage and cumulative number of participants with at least -1 log10 IU/mL change from baseline in BK viral DNA load up to day 267. | Baseline up to day 267 (+/- 14 days) | 
| Assess renal function for Kidney Transplant Recipients (KTRs) with BKV DNAemia throughout the study | Change from baseline in renal function as measured by serum creatinine (SCr) and estimated glomerular filtration rate (e)GFR (by CKD-EPI formula) until end of follow-up. | Baseline through day 267 (+/- 14 days) | 
| Kidney graft lost and biopsy-confirmed BKVAN | Kidney graft lost and biopsy-confirmed BKVAN will be studied by Kaplan-Meier analyses for time to event data. Percentage and cumulative number of participants with progression to BKVAN confirmed by kidney biopsies (using the Banff criteria) prior to first dose, day 141 and an optional biopsy at day 267. Percentage and cumulative incidence of participants developing clinically apparent nephropathy until end of follow-up | Baseline up to day 267 (+/- 14 days) |