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A randomized, double-blind, parallel group, placebo-controlled, multi-center study to assess the safety and tolerability of monthly subcutaneous administrations of a low and high dose cohort of osocimab to ESRD patients on regular hemodialysis

Study to Investigate the Safety of a Drug Called Osocimab at Low and High Doses in Adult Patients With Kidney Failure Requiring Regular Hemodialysis (CONVERT)

859

Overall, approximately 46% of participants were less than 60 years old (mean = 60.3 years; median 61.0 years) and less than 14% of the population was older than 75 years of age. Prior major adverse cardiovascular events (MACE) were reported in 12.8% of participants. The proportion of participants with atrial fibrillation, deep vein thrombosis (DVT), MI, peripheral arterial occlusive disease, PE, and transient ischemic attack) occurred in less than 10% of the overall population. Overall, 37.8% of participants had diabetes mellitus. Acetylsalicylic acid use at baseline was reported in 42.3% of participants.

A total of 859 participants were enrolled, 704 participants were randomized to treatment, and 686 participants were treated: 224 with higher-dose osocimab, 232 with lower-dose osocimab, and 230 with placebo. In the higher-dose osocimab group, the lower-dose osocimab group, and the placebo group, 10, 3, and 5 participants discontinued from the pretreatment period, 30, 33, and 24 participants discontinued from the main treatment phase, 20, 20, and 30 participants discontinued from the extension phase, and 13, 10, and 4 discontinued from the follow-up period. Therefore, 224, 232, and 230 participants completed the pretreatment period, 194, 199, and 206 participants completed the main treatment period, 174, 178, and 176 participants completed the extension treatment period, and 194, 197, and 201 participants completed the follow-up period. All 704 participants assigned to study drug were included in the full analysis set. The safety analysis set included participants who received at least 1 dose of study drug: 224 participants in the higher-dose osocimab group, 232 in the lower-dose osocimab group, and 230 in the placebo group. The pharmacokinetic (PK) analysis set included osocimab-treated participants with at least 1 PK sample in accordance with the PK sampling schedule who had no deviations from the protocol that may have interfered with the evaluation of the PK data: 220 and 226 participants. The PD analysis set included participants with at least 1 PD sample in accordance with the PD sampling schedule who had no deviations from the protocol that may have interfered with the evaluation of the PD data: 224, 232, and 230 participants.

The proportions of participants reporting treatment-emergent AEs (TEAEs) in the overall treatment period (main + extension treatment period) were slightly lower in the placebo group than the higher- and lower-dose osocimab groups (73.0%, 79.5%, and 76.7%, respectively). The most frequently reported TEAE was headache in the osocimab groups (8.5% higher-dose and 9.9% lower-dose) and hypotension in the placebo group (7.8%). There were no dose dependency between the higher- and lower-dose osocimab arms in the occurrence of TEAEs resulting in death (4.0% versus 6.9%). The proportions of participants with treatment-emergent SAEs during the overall treatment period were similar between the higher- and lower-dose groups and the placebo group (27.2%, 28.9%, and 27.4%, respectively). The most frequently reported events were COVID-19 (coronavirus disease 2019), renal transplant, pneumonia, and COVID-19 pneumonia. The proportions of participants who permanently discontinued study drug due to TEAEs were similar between the higher- and lower-osocimab groups and the placebo group: 6.7%, 6.5%, and 8.3%, respectively. The most frequently reported event that led to discontinuation in all groups was renal transplant in 1.8%, 1.3%, and 2.2% of participants, respectively. All other events leading to discontinuation were reported in less than 1.0% of participants in each group. The proportions of participants reporting drug-related TEAEs in the overall treatment period were slightly lower in the placebo group than the higher- and lower-dose osocimab groups (10.0%, 15.6%, and 12.5%, respectively). Each event was reported in less than 2% of participants in each treatment group. By severity, the majority of participants who experienced TEAEs during the overall treatment period had events that were mild or moderate in intensity: 25 (11.2%) participants in the higher-dose group, 30 (12.9%) in the lower-dose group, and 35 (15.2%) in the placebo group experienced severe TEAEs. Most of the severe TEAEs occurred in the system organ classes infections and infestations (most common preferred terms were COVID-19 and COVID-19 pneumonia) and cardiac disorders (all severe cardiac events occurred in 2 or less participants in each treatment group). The proportion of participants experiencing injection site events during the overall treatment period was low: 7.6% in the higher-dose group, 6.0% in the lower-dose group, and 0.4% in the placebo group. The incidence TEAEs of special interest were low. During the overall treatment period, =<1.3% participants in each treatment group experienced thrombocytopenia and =<1.7% participants in the osocimab groups experienced hypersensitivity (none were reported in the placebo group).

Treatment-emergent composite outcome of MB and CRNMB events during the main treatment period was the primary safety endpoint in this study. The cumulative incidence estimates (i.e. the expected proportions of participants with treatment-emergent composite outcome over the course of time taking competing risks into account) were lowest in the higher-dose osocimab group and highest in the placebo group. At 180 days post-randomization, the cumulative incidence risks to experience the composite outcome were 3.57% (90% CI: 1.91-6.04) for higher-dose osocimab, 4.32% (90% CI: 2.48-6.91) for lower-dose osocimab, and 6.09% (90% CI: 3.84-9.04) for placebo. The rate of treatment-emergent composite outcome prior to the competing events until the end of the main treatment period tended to be lower in the higher-dose osocimab group versus placebo (cause-specific HR: 0.59 90% CI: 0.28-1.21; log-rank test p=0.222) than in the lower-dose osocimab group versus placebo (cause-specific HR: 0.72, 90% CI: 0.36-1.42; log-rank test p=0.427). The composite of moderate and severe AEs and SAEs was also a primary safety endpoint with 39.7%, 38.8%, and 32.2% of participants in the osocimab higher-dose group, the osocimab lower-dose group, and in the placebo group experiencing the treatment-emergent composite outcome prior to a competing event until the end of the main treatment period. At 180 days post-randomization, the cumulative incidence risks to experience the composite outcome were 38.84% (90% CI: 33.46-44.17) for higher-dose osocimab, 38.37% (90% CI: 33.10-43.60) for lower-dose osocimab, and 32.17% (90% CI: 27.16-37.28) for placebo. The rate of treatment-emergent composite outcome of moderate and severe AEs and SAEs prior to the competing events until the end of the main treatment period were similar in the osocimab groups versus placebo (higher-dose: cause-specific HR: 1.27 90% CI: 0.98-1.64; log-rank test p=0.128; lower-dose: cause-specific HR: 1.24, 90% CI: 0.96-1.61; log-rank test p=0.166).

Activated partial thromboplastin time (aPTT) and Factor XI (FXI) activity at trough levels. The main PD parameters were aPTT and FXI activity (clotting assay). aPTT and FXI activity were affected by the 2 osocimab dosing regimen in a dose-dependent way. The loading dose provided PD effects at 2, 4, and 30 days that were comparable to those effects observed at comparable time points after the maintenance doses during the entire treatment. This supports that the loading dose/maintenance dose regimen tested lead to stable PD effects supporting once monthly dosing. Specifically, mean aPTT prolongation at 6 months post dose was 1.26 fold for the higher-dose and 1.19 fold for the lower-dose. Mean residual FXI activity at 6 months post dose was 87% for the higher and 94% for the lower osocimab dose.

Compared with placebo, osocimab treatment was not associated with an increased risk of bleeding in a broad spectrum of ESRD patients on hemodialysis and was generally safe and well-tolerated.

No

Myoishi Masashi

Bayer Yakuhin, Ltd.

2-4-9 Umeda, Kita-ku, Osaka, Osaka

byl_ct_contact@bayer.com

Dedicated contact

Bayer Yakuhin, Ltd.

2-4-9 Umeda, Kita-ku, Osaka, Osaka

+81-6-6133-6363

byl_ct_contact@bayer.com

completed

Sept. 01, 2020

Interventional

Interventional (Clinical Trial), Randomized, Parallel Assignment, Masking: Triple (Patitent, Investigator, Outcomes Assessor)

treatment purpose

2

- Participants must be at least 18 years of age
- Patients with end-stage renal disease on hemodialysis (including hemodiafiltration) for >= 3 months, receiving dialysis at least 9 hours a week and stable in the view of the investigator
- Body weight of at least 50 kg
- Male and/or female. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

- Recent (<6 months before screening) clinically significant bleeding
- Hemoglobin (Hb) < 9.0 g/dL at screening
- Platelet count < 100 x 109/L
- aPTT or PT > ULN (upper limit of normal)
- Hepatic disease associated with ALT > 3x ULN, or total bilirubin > 2x ULN with direct bilirubin > 20% of the total
- Sustained uncontrolled hypertension (diastolic blood pressure >= 00 mmHg and/or systolic blood pressure >= 180 mmHg)
- Known intracranial neoplasm, arteriovenous malformation or aneurysm
- Known bleeding disorders e.g. von-Willebrand disease or Hemophilia A, B or C
- Recent (<3 months before screening) thromboembolic event, e.g. acute coronary syndrome, stroke or VTE (except dialysis access thrombosis)
- Recent (<3 months before screening) major surgery or scheduled major surgery during study participation
- Scheduled living donor renal transplant during study participation
- Persistent heart failure as classified by the New York Heart Association (NYHA) classification of 3 or higher
- Receiving antiplatelet therapy except daily ASA =< 150 mg/day
- Receiving anticoagulation in therapeutic doses, other than standard anticoagulation during the hemodialysis procedure

Both

Prevention of Thromboembolic Events in ESRD Patients on Hemodialysis Who Are at Risk for Thromboembolic Events.

investigational material(s)
Generic name etc : BAY 1213790
INN of investigational material : osocimab
Therapeutic category code : 333 Anticoagulants
Dosage and Administration for Investigational material : Single loading dose as subcutaneous abdominal injection followed by monthly maintenance doses. BAY 1213790 Low dose: Loading dose 105 mg, Maintenace dose 52.5 mg. BAY 1213790 High dose: Loading dose 210 mg, Maintenance dose 105 mg.

control material(s)
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : Subcutaneous administration in the same manner as osocimab.

safety
1. Composite of major and clinically-relevant non-major bleeding events as assessed by blinded Central Independent Adjudication Committee (CIAC) [ Time Frame: From the first dose at month 1 and up to 6 months ]
2. Composite of moderate and severe adverse ( AEs) and serious adverse events (SAEs) [ Time Frame: From the first dose at month 1 and up to 6 months ]

exploratory
1. Activated partial thromboplastin time (aPTT) at trough levels [ Time Frame: At baseline and after 6 months ] aPTT will be measured via the kaolin-trigger method (clotting assay)
2. Factor XIa (FXIa) activity at trough levels [ Time Frame: At baseline and after 6 months ] Factor XI activity will be assessed with an aPTT-based coagulation test using FXI deficient plasma

Aug. 21, 2020